Chemical Engines and Methods for Their Use, Especially in the Injection of Highly Viscous Fluids

ABSTRACT

Chemical engines and processes for their use and construction are described. The chemical engines can provide powerful and compact devices, especially autoinjectors for the rapid, powered injection of viscous medicines. Novel formulations and designs of chemical engines and delivery technologies employing the chemical engines are described.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationsNos. 61/713,236 and 61/713,250; both of which were filed Oct. 12, 2012and U.S. Provisional Patent Application No. 61/817,312, filed Apr. 29,2013.

INTRODUCTION

This invention concerns technologies in which a gas is generated via achemical reaction. The forces created the released gas can be harnessedto power useful processes. The chemical reactions are not combustion andavoid many of the problems associated with combustion. Instead, thechemical reactions usually involve the generation of CO₂ frombicarbonate (HCO₃). In general, this technology is termed chemicalengine technology, or simply ChemEngine® as the technology developed byBattelle Memorial Institute is known. The invention is especially usefulfor the delivery of protein therapeutics.

Protein therapeutics is an emerging class of drug therapy that can treata broad range of diseases. Because of their large size and limitedstability, proteins must be delivered by parenteral delivery methodssuch as injection or infusion. For patients suffering from chronicdiseases that require regular treatment, the trend is towardsself-administration by subcutaneous injection, for example in theadministration of insulin by diabetics. Typical subcutaneous injectioninvolves delivery of 1 mL of formulation, but sometimes up to 3 mL, inless than 20 sec. Subcutaneous injection may be carried out with anumber of devices, including syringes, auto-injectors, and peninjectors.

Transitioning therapeutic protein formulations from intravenous deliveryto injection devices like syringes requires addressing challengesassociated with delivering high concentrations of high molecular weightmolecules in a manner that is easy, reliable, and causes minimal pain tothe patient. In this regard, while intravenous bags typically have avolume of 1 liter, the standard volume for a syringe ranges from 0.3milliliters up to 25 milliliters. Thus, depending on the drug, todeliver the same amount of therapeutic proteins, the concentration mayhave to increase by a factor of 40 or more. Also, injection therapy ismoving towards smaller needle diameters and faster delivery times forpurposes of patient comfort and compliance.

Delivery of protein therapeutics is also challenging because of the highviscosity associated with such therapeutic formulations, and the highforces needed to push such formulations through a parenteral device.Formulations with absolute viscosities above 20 centipoise (cP), andespecially above 40-60 centipoise (cP) are very difficult to deliver byconventional spring driven auto-injectors for multiple reasons.Structurally, the footprint of a spring for the amount of pressuredelivered is relatively large and fixed to specific shapes, whichreduces flexibility of design for delivery devices. Next, auto-injectorsare usually made of plastic parts. However, a large amount of energymust be stored in the spring to reliably deliver high-viscosity fluids.This may cause damage to the plastic parts due to creep, which is thetendency of the plastic part to permanently deform under stress. Anauto-injector typically operates by using the spring to push aneedle-containing internal component towards an outer edge of thehousing of the syringe. There is risk of breaking the syringe when theinternal component impacts the housing, due to the high applied forceneeded to inject a high-viscosity fluid. Also, the sound associated withthe impact can cause patient anxiety, reducing future compliance. Thegenerated pressure versus time profile of such a spring drivenauto-injector cannot be readily modified, which prevents users from finetuning pressure to meet their delivery needs.

The force that is required to deliver a given formulation depends onseveral factors including the needle diameter (d), the needle length(L), formulation viscosity (μ), and volumetric flow rate (Q). In thesimplest approximation—one that does not consider frictional forcesbetween the plunger and the barrel—the force is related to the pressuredrop (ΔP) multiplied by the cross-sectional area of the plunger (A). Thepressure drop (ΔP) of a fluid in laminar flow through a needle may bedescribed by the Hagen-Poiseuille equation:

$F = {{\Delta \; {P \cdot A}} = {\frac{128 \cdot \mu \cdot L \cdot Q}{\pi \cdot d^{4}} \cdot A}}$

In a syringe, the force is provided by the user. Reasonable finger forceis considered to be less than 15-20 N for healthy patient populationsand somewhat less for patients with limited dexterity, such as theelderly or those suffering from Rheumatoid arthritis or multiplesclerosis. In typical auto-injectors, the force is provided by a spring.The force provided by a spring decreases linearly with displacement, andthe spring must be chosen so that sufficient force is available tosustain the injection. Viscosities above 20 cP, become difficult todeliver in a reasonable time by the typical spring driven auto-injector:

-   -   Breakage of plastic parts that hold compressed spring; large        energy stored leads to creep    -   Syringe breakage (high initial force)    -   Incomplete doss delivered due to stalling (insufficient final        force)    -   Inflexibility of device designs, including large footprint of        spring        Other sources of energy have been considered for auto-injectors.        One source is the use of an effervescent reaction that creates        pressure on-demand. A study funded by the Office of Naval        Reserve (SoRI-EAS-85-746), entitled “Development of an        On-Demand, Generic, Drug-Delivery System, 1985 described the use        of bicarbonates mixed with acids to generate CO2 that could        drive slow delivery of a drug fluid. These devices were targeted        at slow, long-term delivery over 24 h. Böttger and Böbst        disclosed the use of syringe that uses a chemical-reaction to        deliver fluid (US2011/0092906). Good et al. in “An effervescent        reaction micropump for portable microfluidic systems,” Lab Chip,        2006, 659-666 described formulations intended for micropumps        using various concentrations of tartaric acid and sodium        bicarbonate and different sizes of sodium bicarbonate particles.        However, their invention provides delivery in a manner that the        injection force increases exponentially over time. The prior art        chemical engines do not provide adequate delivery, especially        for conditions where the impact of the expanding volume in the        piston is non-negligible, such as when the reagent volume is        minimized to minimize the engine footprint and overshoot;        without accounting for the expanding volume, chemical engines        can stall during delivery in the same way that springs stall.

The present invention provides solutions to the foregoing problems byemploying improvements to chemical engine technology. In especiallypreferred aspects, processes and devices are described in which achemical engine can be used to comfortably and quickly self-administer ahigh-viscosity fluid with a relatively small injector. These processesand devices could be used to deliver high-concentration protein, orother high viscosity pharmaceutical formulations.

SUMMARY OF THE INVENTION

The invention provides chemical engines and methods of using thechemical engines to drive a fluid. The invention also includes methodsof making chemical engines.

In a first aspect, the invention provides a chemical engine, comprising:a closed container comprising an acid, bicarbonate, water, and aplunger; a mechanism adapted to combine the acid, the water, and thebicarbonate; and further characterized by a power density of at least50,000 W/m³, as measured at a constant nominal backpressure of 40 N, ora power density ratio of at least 1.4 as compared to a controlcomprising a 3:1 molar ratio of sodium bicarbonate and citric acid andhaving a concentration of 403 mg citric acid in 1 g H₂O.

The characterization of the chemical engine by a power density isnecessary because, in view of the variety of factors described herein,it is not possible to define the full breadth of the invention by othermeans. The stated levels of power density were not obtained in priordevices and the claimed levels of power density were not previouslyidentified as either desirable or attainable. This feature bringstogether numerous technical advantages such as providing ease of holdinga powered syringe, that delivers a viscous solution with greater comfortand less risk of breakage than conventional, spring-poweredautoinjectors or previously described gas-powered injectors. The claimedcharacteristic has the additional advantages of ease of measurement andhigh precision of the measured values.

In some preferred embodiments, at least 50 wt % of the bicarbonate is asolid. It has been surprisingly discovered that potassium bicarbonateprovides a faster reaction and generates more CO2 than sodiumbicarbonate under otherwise identical conditions. Thus, in preferredembodiments, a chemical engine comprises at least 50 wt % potassiumbicarbonate. Preferably, the acid is citric acid, and in some preferredembodiments the citric acid is dissolved in water; the configurationwith solid potassium carbonate and citric acid in solution can provideenhanced power density. In some preferred embodiments, the closedcontainer comprises 1.5 mL or less of a liquid. In some preferredembodiments, the closed container has a total internal volume, prior tocombining the acid and the carbonate, or 2 mL or less. In someembodiments, the acid and bicarbonate are present as solids and thewater is separated from the acid and the bicarbonate.

Formulations for chemical engines may be improved by the addition of aconvection agent. Improved pressure profiles may also be provided wherethe bicarbonate comprises a solid mixture of at least two types ofparticle morphologies.

The power density is typically used to describe a latent characteristicof a chemical engine; although, less usually, it can be used to describea system undergoing the chemical reaction. In preferred embodiments,displacement of a plunger or flexible wall in the chemical engine beginswith 2 sec, more preferably within 1 sec of the moment when acid,carbonate and solvent (water) are combined; this moment is the momentwhen the chemical engine is initiated.

In another aspect, the invention provides a chemical engine, comprising:a closed container comprising an acid solution comprising an aciddissolved in water, and bicarbonate, wherein the acid solution isseparated from the solid bicarbonate, and a plunger; a conduitcomprising apertures disposed within the closed container and adaptedsuch that, following initiation, at least a portion of the acid solutionis forced through at least a portion of the apertures. Preferably, thebicarbonate is in particulate form and wherein the conduit comprises atube having one end that is disposed in the solid bicarbonate such that,when the solution is forced through the apertures it contacts the solidbicarbonate particulate. In some preferred embodiments, at least aportion of the bicarbonate is in solid form disposed inside the conduit.In some embodiments, a spring is adapted to force the acid solutionthrough the conduit.

In some preferred embodiments of any aspect of the invention, a chemicalengine has an internal volume of 2 ml or less, in some embodiments, 1.5ml or less, in some embodiments 1.0 ml or less, and in some embodimentsin the range of 0.3 ml to 2 ml, 0.3 ml to 1.5 ml, 0.5 ml to 1.5 ml, or0.7 ml to 1.4 ml.

In another aspect, the invention provides a chemical engine, comprising:

a closed container comprising an acid solution comprising an aciddissolved in water, and potassium bicarbonate, wherein the acid solutionis separated from the potassium bicarbonate, and a plunger; and amechanism adapted to combine the acid solution and the potassiumbicarbonate. In some embodiments, the potassium bicarbonate is mixedwith sodium bicarbonate. The molar ratio of potassium:sodium in thebicarbonate is 100:0, or at least 9, or at least 4, or at least 1; andin some embodiments is at least 0.1, in some embodiments in the range of0.1 to 9; in some embodiments in the range of 0.5 to 2.

In a further aspect, the invention provides a chemical engine,comprising:

a closed container comprising an acid solution comprising an aciddissolved in water, solid bicarbonate particles, and solid particulateconvection agents, wherein the acid solution is separated from the solidbicarbonate, and a plunger; and a mechanism adapted to combine the acidsolution and the solid bicarbonate. Solid particulate convection agentsare present:

in the range of less than 50 mg per ml of combined solution and at alevel selected such that, all other variables being held constant, thegeneration of CO₂ is faster during the first 5 seconds in which the acidsolution and solid bicarbonate are combined than the generation of CO₂in the presence of 50 mg per ml of the particulate convection agents; or

in a concentration of 5 mg to 25 mg per ml of combined solution. In someembodiments, 5 mg to 15 mg or 5 mg to 10 mg per ml of combined solution.

The term “combined solution” means the volume of liquid after the acidsolution and solid bicarbonate are mixed. The term “solid bicarbonate”means that there is at least some solid bicarbonate present, althoughthere could also be some liquid phase (typically aqueous phase) presentwith the bicarbonate. In some preferred embodiments, the bicarbonate isat least 10% present as a solid, in some embodiments at least 50%, atleast 90% or substantially 100% present as a solid in the chemicalengine prior to combination with the acid solution.

The term “solid convection agents” refers to solid particulates thathave a lower solubility than the solid bicarbonate, preferably at leasttwo times slower dissolving than the solid bicarbonate, more preferablyat least 10 times slower dissolving than the solid bicarbonate under theconditions present in the chemical engine (or, in the case of theunreacted chemical engine, defined at standard temperature andpressure); in some embodiments at least 100 times slower. The “solidconvection agents” preferably have a density, as measured by mercuryporisimetry at ambient pressure, that is at least 5%, more preferably atleast 10% different from water or the solution in which the convectionagents are dispersed. The “solid convection agents” preferably have adensity that is at least 1.05 g/ml; more preferably at least 1.1 g/ml;in some embodiments at least 1.2 g/ml, and in some embodiments in therange of 1.1 to 1.5 g/ml. Alternatively, the “solid convection agents”may have a density that is less than water, for example 0.95 g/ml orless, 0.9 g/ml or less, and in some embodiments 0.8 to 0.97 mg/ml. Inpreferred embodiments, the convection agents are used in a system thatis not supersaturated; this is typically in the case in short time scalesystems such as an autojector operating over 1 minute or less,preferably 30 seconds or less, more preferably 20 seconds or less, andstill more preferably 10 seconds or 5 seconds or less. Thus, thediatomaceous earth formulations of this invention differ from the systemof LeFevre in U.S. Pat. No. 4,785,972 which uses large quantities ofdiatomaceous earth to act as a nucleating agent in a supersaturatedsolution over a large time scale. The present invention includes methodsof operating a chemical engine over a short period utilizing aconvection agent in which greater than 50% of the bicarbonate (morepreferably at least 70% or at least 90%) is converted to gaseous carbondioxide within a short time scale of a minute or less. Preferably, thediatomaceous earth or other convection agent is present at a level thatis at least 50 mass % less than would be used to optimize CO₂ dischargefrom a supersaturated system that is designed to release gaseous CO₂over more than 30 minutes of the CO₂ being formed in solution.

In another aspect, the invention provides a chemical engine, comprising:a closed container comprising an acid solution comprising an aciddissolved in water, and solid bicarbonate particles, wherein the acidsolution is separated from the solid bicarbonate, and a plunger; amechanism adapted to combine the acid solution and the solidbicarbonate; wherein the solid bicarbonate particles comprise a mixtureof particle morphologies. In some embodiments, the solid bicarbonateparticles are derived from at least two different sources, a firstsource and a second source, and wherein the first source differs fromthe second source by at least 20% in one or more of the followingcharacteristics: mass average particle size, surface area per mass,and/or solubility in water at 20 C as measured by the time to completedissolution into a 1 molar solution in equally stirred solutions usingthe solvent in the chemical engine (typically water).

In a further aspect, the invention provides a method of ejecting aliquid medicament from a syringe, comprising: providing a closedcontainer comprising an acid solution comprising an acid dissolved inwater, and bicarbonate, wherein the acid solution is separated from thebicarbonate, and a plunger; wherein the acid solution and thebicarbonate in the container define a latent power density; wherein theplunger separates the closed container from a medicament compartment;combining the acid solution and the bicarbonate within the closedcontainer; wherein the acid solution and the bicarbonate react togenerate CO₂ to power the plunger, which, in turn, pushes the liquidmedicament from the syringe; wherein pressure within the containerreaches a maximum within 10 seconds after initiation, and wherein, after5 minutes, the latent power density is 20% or less of the initial latentpower density, and wherein, after 10 minutes, the pressure within theclosed container is no more than 50% of the maximum pressure. In somepreferred embodiments, the closed container further comprises a CO₂removal agent that removes CO₂ at a rate that is at least 10 timesslower than the maximum rate at which CO₂ is generated in the reaction.

Disclosed in some embodiments is a device for delivering a fluid bychemical reaction, comprising: a reagent chamber having a plunger at anupper end and a one-way valve at a lower end, the one-way valvepermitting exit from the reagent chamber; a reaction chamber having theone-way valve at an upper end and a piston at a lower end; and a fluidchamber having the piston at an upper end, wherein the piston moves inresponse to pressure generated in the reaction chamber such that thevolume of the reaction chamber increases and the volume of the fluidchamber decreases.

In any of the inventive aspects, the devices or methods can becharacterized by one or more of the following characteristics. Thereaction chamber preferably has a volume of at most 1.5 cm³, in someembodiments at most 1.0 cm³. Preferably, the fluid chamber contains ahigh-viscosity fluid having an absolute viscosity of from about 5centipoise to about 1000 centipoise, or a viscosity of at least 20,preferably at least 40 centipoise, in some embodiments in the range of20 to 100 cP. The reagent chamber may contain a solvent and/or abicarbonate or acid dissolved in the solvent. The solvent preferablycomprises water. In some preferred embodiments, the reaction chamber maycontain a dry acid powder and a release agent. In some embodiments, theacid powder is citrate and the release agent is sodium chloride.Alternatively, the reaction chamber can contain at least one or at leasttwo chemical reagents that react with each other to generate a gas. Thereaction chamber may further comprise a release agent.

In some embodiments, an upper chamber may contain a solvent. The lowerchamber may contain at least two chemical reagents that react with eachother to generate a gas. The lower chamber may, for example, contain abicarbonate powder and an acid powder.

The devices may include a piston comprising a push surface at the lowerend of the reaction chamber, a stopper at the upper end of the fluidchamber, and a rod connecting the push surface and the stopper. A pistonis one type of plunger; however, a plunger often does not contain a rodthat connects a push surface and a stopper.

A plunger may include a thumbrest, as well as a pressure lock thatcooperates with the upper chamber to lock the plunger in place afterbeing depressed. The pressure lock can be proximate the thumbrest andcooperate with an upper surface of the upper chamber. A plunger thatincludes a thumbrest can be termed an initiation plunger since itfrequently is employed to cause mixing to occur in which an acid and acarbonate are combined in solution.

In some preferred embodiments, a chemical engine may comprise a lowerchamber defined by the one-way valve, a continuous sidewall, and apiston, the one-way valve and the sidewall being fixed relative to eachother such that the volume of the lower chamber changes only throughmovement of the piston.

In preferred embodiments, the upper chamber, the lower chamber, and thefluid chamber are cylindrical and are coaxial. The upper chamber, thelower chamber, and the fluid chamber can be separate pieces that arejoined together to make the device. A one-way valve can feed a balloonin the lower chamber, the balloon pushing the piston. Sometimes, eitherthe upper chamber or the lower chamber contains an encapsulated reagent.

Also described in various embodiments is a device for delivering a fluidby chemical reaction, comprising: an upper chamber having a seal at alower end; a lower chamber having a port at an upper end, a ring ofteeth at the upper end having the teeth oriented towards the seal of theupper chamber, and a piston at a lower end; and a fluid chamber havingthe piston at an upper end; wherein the upper chamber moves axiallyrelative to the lower chamber; and wherein the piston moves in responseto pressure generated in the lower chamber such that the volume of thereaction chamber increases and the volume of the fluid chamberdecreases.

The piston may include a head and a balloon that communicates with theport. The ring of teeth may surround the port. The upper chamber maytravel within a barrel of the device. Sometimes, the upper chamber isthe lower end of a plunger. The plunger may include a pressure lock thatcooperates with a top end of the device to lock the upper chamber inplace after being depressed. Alternatively, the top end of the devicecan include a pressure lock that cooperates with a top surface of theupper chamber to lock the upper chamber in place when moved sufficientlytowards the lower chamber.

A fluid chamber may contain a high-viscosity fluid having a viscosity ofat least 5 or at least 20 or at least 40 centipoise. An upper chambermay contain a solvent. A lower chamber may contain at least two chemicalreagents that react with each other to generate a gas. Sometimes, theupper chamber, the lower chamber, and the fluid chamber are separatepieces that are joined together to make the device. In yet otherembodiments, either the upper chamber or the lower chamber contains anencapsulated reagent.

Also described herein is a device for delivering a fluid by chemicalreaction, comprising: an upper chamber; a lower chamber having a pistonat a lower end; a fluid chamber having the piston at an upper end; and aplunger comprising a shaft that runs through the upper chamber, astopper at a lower end of the shaft, and a thumbrest at an upper end ofthe shaft, the stopper cooperating with a seat to separate the upperchamber and the lower chamber; wherein pulling the plunger causes thestopper to separate from the seat and create fluid communication betweenthe upper chamber and the lower chamber; and wherein the piston moves inresponse to pressure generated in the lower chamber such that the volumeof the reaction chamber increases and the volume of the fluid chamberdecreases.

The present disclosure also relates to devices for delivering a fluid bychemical reaction, comprising: a reaction chamber divided by a barrierinto a first compartment and a second compartment, the first compartmentcontaining at least two dry chemical reagents that can react with eachother to generate a gas, and the second compartment containing asolvent; and a fluid chamber having an outlet; wherein fluid in thefluid chamber exits through the outlet in response to pressure generatedin the reaction chamber.

The pressure generated in the reaction chamber may act on a piston orplunger at one end of the fluid chamber to cause fluid to exit throughthe outlet of the fluid chamber.

In some embodiments, the reaction chamber includes a flexible wall,proximate to the fluid chamber; and wherein the fluid chamber is formedfrom a flexible sidewall, such that pressure generated in the reactionchamber causes the flexible wall to expand and compress the flexiblesidewall of the fluid chamber, thus pushing fluid to exit through theoutlet.

The reaction chamber and the fluid chamber may be surrounded by ahousing. Sometimes, the reaction chamber and the fluid chamber areside-by-side in the housing. In other embodiments, a needle extends froma bottom of the housing and is fluidly connected to the outlet of thefluid chamber; and the reaction chamber is located on top of the fluidchamber.

A reaction chamber may be defined by the one-way valve, a sidewall, anda plunger, the one-way valve and the sidewall being fixed relative toeach other such that the volume of the reaction chamber changes onlythrough movement of the plunger.

Also disclosed in various embodiments is a device for dispensing a fluidby chemical reaction, comprising: a reaction chamber having first andsecond ends; a plunger at a first end of the reaction chamber, theplunger being operative to move within the device in response to apressure generated in the reaction chamber; and a one-way valve at thesecond end of the reaction chamber permitting entry into the reactionchamber.

The device may comprise a reagent chamber on an opposite side of theone-way valve. The reagent chamber may contain a solvent and abicarbonate powder dissolved in the solvent. The solvent can comprisewater. The device may further comprise a plunger at an end of thereagent chamber opposite the one-way valve. The plunger may cooperatewith the reagent chamber to lock the initiation plunger in place afterbeing depressed.

Also disclosed in various embodiments is a device for delivering a fluidby chemical reaction, comprising: a barrel which is divided into areagent chamber, a reaction chamber, and a fluid chamber by a one-wayvalve and a piston (or other type of plunger); and an initiation plungerat one end of the reagent chamber; wherein the one-way valve is locatedbetween the reagent chamber and the reaction chamber; and wherein thepiston separates the reaction chamber and the fluid chamber, the piston(or other type of plunger) being moveable to change the volume ratiobetween the reaction chamber and the fluid chamber.

The present disclosure also relates to a device for delivering a fluidby chemical reaction, comprising: a barrel containing a reaction chamberand a fluid chamber which are separated by a moveable piston; and athermal source for heating the reaction chamber. The reaction chambermay contain at least one chemical reagent that generates a gas uponexposure to heat. The at least one chemical reagent can be2,2′-azobisisobutyronitrile. The generated gas can be nitrogen gas.

The present disclosure also describes a device for delivering a fluid bychemical reaction, comprising: a barrel containing a reaction chamberand a fluid chamber which are separated by a moveable piston; and alight source that illuminates the reaction chamber. The reaction chambermay contain at least one chemical reagent that generates a gas uponexposure to light. The at least one chemical reagent can comprise silverchloride.

The initiation of a gas generating reaction in a chemical engine can beperformed by dissolving at least two different chemical reagents in asolvent. The at least two chemical reagents can include a chemicalcompound having a first dissolution rate and the same chemical compoundhaving a second different dissolution rate. The dissolution rates can bevaried by changing the surface area of the chemical compound, or byencapsulating the chemical compound with a coating to obtain thedifferent dissolution rate.

The pressure versus time profile from a gas generating may include aburst in which the rate of gas generation increases at a rate fasterthan the initial generation of gas.

The reaction chamber may contain a dry acid reagent, with a solventcontaining a predissolved bicarbonate (or a predissolved acid) beingadded to the reaction chamber from a reagent chamber on an opposite sideof the one-way valve to initiate the reaction. The reaction chamber canfurther comprise a release agent, such as sodium chloride. The solventmay comprise water. In some preferred embodiments, the dry acid reagentis a citric acid powder or an acetic acid powder. The gas produced ispreferably carbon dioxide.

Also described herein are a device for delivering a fluid by chemicalreaction, comprising: a barrel containing a reagent chamber, a reactionchamber, and a fluid chamber; wherein the reagent chamber is locatedwithin a push button member at a top end of the barrel; a plungerseparating the reagent chamber from the reaction chamber; a springbiased to push the initiation plunger into the reagent chamber when thepush button member is depressed; and a piston separating the reactionchamber from the fluid chamber, wherein the piston moves in response topressure generated in the reaction chamber. The push button member cancomprise a sidewall closed at an outer end by a contact surface, a lipextending outwards from an inner end of the sidewall, and a sealingmember proximate a central portion on an exterior surface of thesidewall. The barrel may include an interior stop surface that engagesthe lip of the push button member.

The initiation plunger may comprise a central body having lugs extendingradially therefrom, and a sealing member on an inner end which engages asidewall of the reaction chamber. The interior surface of the pushbutton member can include channels for the lugs.

A reaction chamber may be divided into a mixing chamber and an arm by aninterior radial surface, the interior radial surface having an orifice,and the piston being located at the end of the arm.

As a general feature a reaction chamber sometimes includes a gaspermeable filter covering an orifice that allows gas to escape after aplunger has been moved to force fluid out a fluid chamber. This featureprovides a release for excess gas.

The barrel can be formed from a first piece and a second piece, thefirst piece including the reagent chamber and the reaction chamber, andthe second piece including the fluid chamber. The invention includesmethods of making injectors comprising the assembly of the first andsecond piece into an injector or injector component.

Also disclosed in different embodiments is an injection device fordelivering a pharmaceutical fluid to a patient by means of pressureproduced by an internal chemical reaction, comprising: a reagent chamberhaving an activator at an upper end and a one-way valve at a lower end,the one-way valve permitting exit of a reagent from the reagent chamberinto a reaction chamber upon activation; the reaction chamberoperatively connected to the reagent chamber, having means for receivingthe one-way valve at an upper end and a piston at a lower end; and afluid chamber operatively connected to the reaction chamber, havingmeans for receiving the piston at an upper end, wherein the piston movesin response to pressure generated in the reaction chamber such that thevolume of the reaction chamber increases and the volume of the fluidchamber decreases.

It is intended that, in various embodiments, the invention includes allcombinations and permutations of the various features that are describedherein. For example, the formulations described herein can be employedin any of the devices as would be understood by a skilled person readingthese descriptions. Likewise, for every device described herein, thereis a corresponding method of using the device to deliver a viscousfluid, typically a medicant. The invention also includes methods ofmaking the devices comprising assembling the components. The inventionfurther includes the separate chemical engine component and kitsincluding the chemical engine and other components that are assembledinto an injector. The invention may be further characterized by themeasurements described herein; for example, the power densitycharacteristic or any other measured characteristics described in thefigures, examples or elsewhere. For example, characterized by an upperor lower limit or range established by the measured values describedherein.

Various aspects of the invention are described using the term“comprising;” however, in narrower embodiments, the invention mayalternatively be described using the terms “consisting essentially of”or, more narrowly, “consisting of.”

In any of the chemical engines, there can be an initiation plunger thatis typically directly or indirectly activated to initiate the gasgeneration in the chemical engine; for example, the cause an acid andbicarbonate to combine in solution and react to generate CO₂.Preferably, the chemical engine comprises a feature (such as lugs) thatlock the initiator plunger in place so that the reaction chamber remainsclosed to the atmosphere and does not lose pressure except to move aplunger to force a fluid out of the fluid compartment.

In various aspects, the invention can be defined as a formulation,injector, method of making a formulation or injector (typicallycomprising an injector body, an expansion compartment, a plunger (forexample, a piston), and a viscous fluid component that is preferably amedicant. Typically, of course, a needle is connected to the medicamentcompartment. In some embodiments, the expansion compartment can bereleasably attached such that the expansion compartment piece (alsocalled the reaction chamber) can be detached from medicamentcompartment. In some aspects, the invention can be defined as a methodof pushing a solution through a syringe, or a method of administering amedicament, or a system comprising apparatus plus formulation(s) and/orreleased gas (typically CO₂). Medicaments can be conventional medicinesor, in preferred embodiments, biologic(s) such as proteins. Any of theinventive aspects can be characterized by one feature or any combinationof features that are described anywhere in this description.

Preferred aspects of the invention provide a chemical engine that canprovide

-   -   Delivery of viscous fluids (e.g. greater than 20 cP) with a flow        rate of 0.06 mL/sec or higher    -   Energy on demand to eliminate the need to store energy    -   Minimal start-up forces to prevent syringe breakages    -   Relatively constant pressure through-out the injection event to        prevent stalling    -   Tunable pressure or pressure profile, depending on the viscosity        of the fluid or user requirements        Our invention provides a gas-generating chemical-reaction to        create pressure on-demand that may be used to deliver        pharmaceutical formulations by parenteral delivery. The pressure        can be produced by combining two reactive materials that        generate a gas. An advantage of our gas-generating reaction over        prior art is that this can be done in a manner that realizes        rapid delivery (less than 20 sec) of fluids with viscosity        greater than 20 cP and minimize the packaging space required,        while maintaining a substantially flat pressure versus time        profile as shown in the Examples. A further advantage of our        invention is that pressure versus time profile can be modified        for different fluids, non-Newtonian fluids, patient needs, or        devices.

BRIEF DESCRIPTION OF THE DRAWINGS

The following is a brief description of the drawings, which arepresented for the purposes of illustrating the exemplary embodimentsdisclosed herein and not for the purposes of limiting the same.

FIG. 1 is a diagram of a chemical reaction that produces a gas formoving a piston within a chamber.

FIG. 2 is a diagram of a first embodiment of a device for delivering afluid by chemical reaction. The chemical reaction here is generated whentwo dry chemical reagents are dissolved in a solvent and react. Thisfigure shows the device in a storage state, where the dry reagents areseparated from the solvent.

FIG. 3 is a diagram showing the device of FIG. 2 after the dry reagentsare combined with the solvent.

FIG. 4 is diagram showing the device of FIG. 2 with the piston beingpushed by gas pressure to deliver the fluid.

FIG. 5 is a diagram showing another exemplary embodiment of a device fordelivering a fluid by chemical reaction of two reagents in a solvent.This device is made in four separate pieces that are joined together toform a combined device similar to that shown in FIG. 2.

FIG. 6 is a diagram of a first embodiment of a device for delivering afluid by chemical reaction. The chemical reaction here is generated whena chemical reagent is exposed to heat. The device includes a thermalsource.

FIG. 7 is a side cross-sectional view of a first exemplary embodiment ofan injection device. This embodiment uses a one-way valve to create twoseparate chambers.

FIG. 8 is a cross-sectional perspective view of the engine in anexemplary embodiment of FIG. 7.

FIG. 9 is a side cross-sectional view of a second exemplary embodimentof an injection device. This embodiment uses a seal to create twoseparate chambers, and a ring of teeth to break the seal.

FIG. 10 is a cross-sectional perspective view of the engine in thesecond exemplary embodiment of FIG. 9.

FIG. 11 is a side cross-sectional view of a third exemplary embodimentof an injection device. In this embodiment, pulling the handle upwards(i.e. away from the barrel of the device) breaks the seal between twoseparate chambers. This figure shows the device prior to pulling thehandle upwards.

FIG. 12 is a cross-sectional perspective view of the engine in the thirdexemplary embodiment of FIG. 11 prior to pulling the handle upwards.

FIG. 13 is a cross-sectional perspective view of the engine in the thirdexemplary embodiment of FIG. 11 after pulling the handle upwards.

FIG. 14 is a side cross-sectional view of an exemplary embodimentshowing the engine using an encapsulated reagent. This figure shows thedevice in a storage state.

FIG. 15 is a side cross-sectional view of the exemplary embodimentshowing the engine using an encapsulated reagent. This figure shows thedevice in a use state.

FIG. 16 is a perspective see-through view of a first exemplaryembodiment of a patch pump that uses a chemical reaction to injectfluid. Here, the engine and the fluid chamber are side-by-side, and bothhave rigid sidewalls.

FIG. 17 is a perspective see-through view of a second exemplaryembodiment of a patch pump that uses a chemical reaction to injectfluid. Here, the engine is on top of the fluid chamber, and both have aflexible wall. The engine expands and presses the fluid chamber. Thisfigure shows the patch pump when the fluid chamber is empty and prior touse.

FIG. 18 is a perspective see-through view of the patch pump of FIG. 17,where the fluid chamber is filled.

FIG. 19 is a side cross-sectional view of another exemplary embodimentof a syringe that uses a gas-generating chemical reaction. Here, astopper is biased by a compression spring to travel through the reagentchamber and ensure its contents are emptied into the reaction chamber.

FIG. 20 is a bottom view showing the interior of the push button memberin the syringe of FIG. 19.

FIG. 21 is a top view of the stopper used in the syringe of FIG. 19.

FIG. 22 is a graph showing the pressure versus time profile for deliveryof silicone oil when different amounts of water are injected into areaction chamber. The y-axis is Gauge Pressure (Pa), and the x-axis isTime (sec). The plot shows results for conditions where three differentamounts of water were used—0.1 mL, 0.25 mL, and 0.5 mL.

FIG. 23 is a graph showing the volume versus time profile for deliveryof 73 cP silicone oil when a release agent (NaCl) is added to thereaction chamber. The y-axis is Volume (ml), and the x-axis is Time(sec).

FIG. 24 is a volume vs. time graph for delivery of a 73 cP siliconefluid in which the use of modifying or mixing bicarbonate morphology isshown: reaction chamber contains 100% as received, 100% freeze-dried,75% as-received/25% freeze dried, or 50% as-received/50% freeze dried.

FIG. 25 is a pressure vs. time graph for delivery of a 73 cP siliconefluid in which the use of modifying or mixing bicarbonate morphology isshown: reaction chamber contains 100% as received, 100% freeze-dried,75% as-received/25% freeze dried, or 50% as-received/50% freeze dried.

FIG. 26 is a normalized pressure vs. time graph delivery of a 73 cPsilicone fluid during an initial time period. The use of modifying ormixing bicarbonate morphology is shown: reaction chamber contains 100%as received, 100% freeze-dried, 75% as-received/25% freeze dried, or 50%as-received/50% freeze dried.

FIG. 27 is a normalized pressure vs. time graph delivery of a 73 cPsilicone fluid during a second time period. The reaction chambercontained bicarbonates with different morphology or mixed morphology:100% as received, 100% freeze-dried, 75% as-received/25% freeze dried,and 50% as-received/50% freeze dried.

FIG. 28 is a volume vs. time graph for delivery of a 73 cP siliconefluid in which the use of reagents with different dissolution rate orstructure is shown. The engine contained either 100% as-received bakingsoda and citric acid powder, 100% alka seltzer adjusted for similarstoichiometric ratio, 75% as-received powders/25% Alka Seltzer, 50%, 25%as-received powders/75% alka seltzer.

FIG. 29 is a volume vs. time graph for delivery of a 73 cP siliconefluid in which the use of reagents with different dissolution rate orstructure is shown. The engine contained either 100% as-received bakingsoda and citric acid powder, 100% alka seltzer adjusted for similarstoichiometric ratio, 75% as-received powders/25% Alka Seltzer, 50%, 25%as-received powders/75% alka seltzer.

FIG. 30 is a pressure vs. time graph for the delivery of a 1 cP waterfluid in which the use of reagents with different dissolution rate orstructure is shown. The engine contained either 100% as-received bakingsoda and citric acid powder, 100% alka seltzer adjusted for similarstoichiometric ratio, 75% as-received powders/25% Alka Seltzer, 50%, 25%as-received powders/75% alka seltzer.

FIG. 31 is a normalized pressure vs. time graph for delivery of a 73 cPsilicone fluid in which the use of reagents with different dissolutionrate or structure is shown. The engine contained either 100% as-receivedbaking soda and citric acid powder, 100% alka seltzer adjusted forsimilar stoichiometric ratio, 75% as-received powders/25% Alka Seltzer,50%, 25% as-received powders/75% alka seltzer. The pressure isnormalized by normalizing the curves in FIG. 29 to their maximumpressure.

FIG. 32 is a normalized pressure vs. time graph expanding the first 3seconds of FIG. 31.

FIG. 33 is a volume vs. time graph for delivery of a 73 cP siliconefluid in which the reaction chamber contained either sodium bicarbonate(BS), potassium bicarbonate, or a 50/50 mixture.

FIG. 34 is a pressure vs. time graph for the third set of tests;delivery of a 73 cP silicone fluid in which the reaction chambercontained either sodium bicarbonate (BS), potassium bicarbonate, or a50/50 mixture.

FIG. 35 is a reaction rate graph for the third set of tests; delivery ofa 73 cP silicone fluid in which the reaction chamber contained eithersodium bicarbonate (BS), potassium bicarbonate, or a 50/50 mixture.

FIG. 36 is a volume vs. time graph for a fourth set of tests forsilicone oil.

FIG. 37 illustrates a conduit with apertures that may be used to delivera solution into a reaction chamber.

FIG. 38 shows the measured pressure versus time profile for a chemicalengine using mixed sodium and potassium bicarbonate delivering siliconeoil through a 19 mm long and 27 gauge thin wall needle.

FIG. 39. Shows volume versus delivery time for a control (No NaCl) and asystem using solid NaCl as a nucleating agent (NaCl).

FIG. 40 shows the force versus time profile from a two differentchemical engines delivering 1 mL of 50 cP fluid through a 27 gauge thinwall needle (1.9 cm long).

FIG. 41 shows the force versus time profile from a two differentchemical engines (Formulation 3 and 4) delivering 3 mL of 50 cP fluidthrough a 27 gauge thin wall needle (1.9 cm long).

FIG. 42 shows the force versus time profile from chemical engine(Formulation 5) delivering 3 mL of 50 cP fluid through a 27 gauge thinwall needle (1.9 cm long).

FIG. 43 shows the pressure profiles at constant for the compositionsdescribed on the right-hand side of the figure. The observed pressureincreased in the order control<nucleating surface<<Expancelparticles<oxalic acid<diatomaceous earth<calcium oxalate.

FIG. 44 shows the similarity of the effect of vibration and addeddiatomaceous earth in enhancing gas generation.

FIG. 45 illustrates displacement of a viscous fluid powered by achemical engine containing potassium bicarbonate, citric acid and 5, 10or 50 mg of diatomaceous earth acting as a convection agent.

FIG. 46 schematically illustrates apparatus for measuring the powerdensity of a chemical engine.

GLOSSARY

Chemical engine—a chemical engine generates a gas through a chemicalreaction and the generated gas is used to power another process.Typically, the reaction is not combustion, and in many preferredembodiments the chemical engine is powered by the generation of CO₂ fromthe reaction of a carbonate (typically sodium or, preferably, potassiumcarbonate) with an acid, preferably citric acid.

In the context of a chemical engine, a closed container prevents escapeof gas to the atmosphere so that the force of the generated gas can beapplied against a plunger. In the assembled device (typically aninjector) the plunger is moved by the generated gas and forces fluid outof the fluid compartment. In many embodiments, the container is closedat one end by a one way valve, surrounded by chamber walls in thedirections perpendicular to the central axis, and closed at the otherend by a moveable plunger.

Viscosity can be defined in two ways: “kinematic viscosity” or “absoluteviscosity.” Kinematic viscosity is a measure of the resistive flow of afluid under an applied force. The SI unit of kinematic viscosity ismm²/sec, which is 1 centistoke (cSt). Absolute viscosity, sometimescalled dynamic or simple viscosity, is the product of kinematicviscosity and fluid density. The SI unit of absolute viscosity is themillipascal-second (mPa-sec) or centipoise (cP), where 1 cP=1 mPa-sec.Unless specified otherwise, the term viscosity always refers to absoluteviscosity. Absolute viscosity can be measured by capillary rheometer,cone and plate rheometer, or any other known method.

Fluids may be either Newtonian or non-Newtonian. Non-Newtonian fluidsshould be characterized at different shear rates, including one that issimilar to the shear rate of the injection. In this case, the viscosityof the fluid can be approximated using the Hagen-Poiseuille equation,where a known force is used for injection through a known needlediameter and length, at known fluid rate. The invention is suitable foreither Newtonian or non-Newtonian fluids.

A plunger (also called an “expansion plunger”) is any component thatmoves or deforms in response to CO₂ generated in the chemical engine andwhich can transmit force, either directly or indirectly, to a liquid ina compartment that is either adjacent to or indirectly connected to thechemical engine. For example, the plunger could push against a pistonthat, in turn, pushes against a liquid in a syringe. There are numeroustypes of plungers described in this application and in the prior art,and the inventive formulations and designs are generally applicable to amultitude of plunger types.

An initiation plunger is a moveable part that is used to initiate areaction, usually by directly or indirectly causing the combination ofacid, carbonate and water. Preferably, the initiation plunger locks intoplace to prevent any loss of pressure and thus direct all the generatedpressure toward the fluid to be ejected from the fluid chamber.

The term “parenteral” refers to a delivery means that is not through thegastrointestinal tract, such as injection or infusion.

The pressure versus time profile may include a burst, where burst isdescribed as a second increase in pressure during the delivery profile.

The processes of the present disclosure can be used with both manualsyringes or auto-injectors and is not limited to cylindrical geometries.The term “syringe” is used interchangeably to refer to manual syringesand auto-injectors of any size or shape. The term “injection device” isused to refer to any device that can be used to inject the fluid into apatient, including for example syringes and patch pumps. In preferredembodiments, any of the chemical engines described herein may be part ofan injector and the invention includes these injectors.

DETAILED DESCRIPTION

FIG. 1 illustrates the generation of pressure by a chemical reaction foruse in delivering a pharmaceutical formulation by injection or infusion.Referring to the left hand side of the figures, one or more chemicalreagents 100 are enclosed within a reaction chamber 110. One side of thechamber can move relative to the other sides of the chamber, and acts asa piston 120. The chamber 110 has a first volume prior to the chemicalreaction.

A chemical reaction is then initiated within the chamber, as indicatedby the “RXN” arrow. A gaseous byproduct 130 is generated at some rate,n(t), where n represents moles of gas produced and t represents time.The pressure is proportional to the amount of gaseous byproduct 130generated by the chemical reaction, as seen in Equation (1):

P{t)−[n{t)·T]I V  (1)

In Equation (1), T represents temperature and V represents the volume ofthe chamber 110.

The volume of the chamber 110 remains fixed until the additional forcegenerated by the gas pressure on the piston 120 exceeds that needed topush the fluid through a syringe needle. The necessary force depends onthe mechanical components present in the system, e.g. frictional forcesand mechanical advantages provided by the connector design, the syringeneedle diameter, and the viscosity of the fluid.

Once the minimum pressure required to move the piston 120 is exceeded,the volume of the reaction chamber 110 begins to increases. The movementof the piston 120 causes delivery of fluid within the syringe to begin.The pressure in the chamber 110 depends on both the rate of reaction andthe rate of volume expansion, as represented by Equation (1).Preferably, sufficient gas is generated to account for the volumeexpansion, while not generating too much excess pressure. This can beaccomplished by controlling the rates of reaction and gas release in thechamber 110.

The pressure build-up from the chemical-reaction produced gaseousbyproduct 130 can be used to push fluid directly adjacent to the piston120 through the syringe. Pressure build-up may also push fluid in anindirect fashion, e.g., by establishing a mechanical contact between thepiston 120 and the fluid, for example by a rod or shaft connecting thepiston 120 to a stopper of a prefilled syringe that contains fluid.

The one or more chemical reagents 100 are selected so that uponreaction, a gaseous byproduct 130 is generated. Suitable chemicalreagents 100 include reagents that react to generate a gaseous byproduct130. For example, citric acid (C₆H₈O₇) or acetic acid (C₂H₄O₂) willreact with sodium bicarbonate (NaHCO₃) to generate carbon dioxide, CO₂,which can be initiated when the two reagents are dissolved in a commonsolvent, such as water. Alternatively, a single reagent may generate agas when triggered by an initiator, such as light, heat, or dissolution.For, example, the single reagent 2,2′-azobisisobutyronitrile (AIBN) canbe decomposed to generate nitrogen gas (N₂) at temperatures of 50°C.-65° C. The chemical reagent(s) are selected so that the chemicalreaction can be easily controlled.

One aspect of the present disclosure is the combination of variouscomponents to result in (i) enough force to deliver a viscous fluid in ashort time period, e.g. under 20 s, and (ii) in a small package that iscompatible with the intended use, i.e. driving a syringe. In time, size,and in force must all come together to achieve the desired injection.The package size for the chemical engine is defined by the volume of thereagents, including solvents; this is measured at standard conditions(25 C, 1 atm) after all components have been mixed and CO₂ released.

The molar concentration of CO₂ versus H₂CO₃ is given by pH. The pKa ofH₂CO₃ is 4.45. For pH well below this value, the percentage of CO2 toH2CO3 is almost 100%. For pH close to the pKa (e.g. 4.5 to 6.5), thevalue will decrease from 90% to 30%. For pH greater than 7, the systemwill consist of mostly H₂CO₃ and no CO₂. Suitable acids should thusprovide buffering of the system to maintain the pH below 4.5 throughoutthe duration of the injection event. The chemical reaction need not goto 100% conversion during the injection event (e.g., within 5 seconds,or within 10 seconds or within 20 seconds) in the time frame of theinjection event, but generally, to minimize generation of excesspressure, conversion should approach at least 30-50%; where conversionis defined as the molar percentage of acid that has been reacted, and insome embodiments in the range of 30 to 80%, in some embodiments in therange of 30 to 50%. In some embodiments, conversion of the CO₂ reactant(such as sodium or potassium bicarbonate) is at least 30%, preferably atleast 50%, or at least 70% and in some embodiments less than 95%.

Acids that are liquid at room temperature such as glacial acetic acid(pKa1 4.76) and butyric acid (pKa 4.82) are suitable. Preferred acidsare organic acids that are solid at room temperature; these acids havelittle odor and do not react with the device. In addition, they can bepackaged as powders with different morphology or structure to provide ameans of controlling dissolution rate. Preferred acids include citricacid (pH: 2.1 to 7.2 (pKa: 3.1; 4.8; 6.4), oxalic acid (pH: 0.3 to 5.3[pKa: 1.3; 4.4]), tartartic acid (pH: 2 to 4; [pKa1=2.95; pKa2=4.25]),and phthalic acid (pH: 1.9-6.4 [pKa: 2.9; 5.4]). In experiments withadded HCl. It was surprisingly discovered that reducing the pH to 3 didnot speed the release of CO₂.

In some preferred embodiments, citric acid is used in systems where theinjection event occurs at reaction conversions between 15 to 50%. It maybe desirable to take advantage of the rapid rate of CO₂ build-up, andthus pressure, that occurs at low conversion. Due to the bufferingbehavior of this acid, the percentage of CO₂ to H₂CO₃ created during thereaction will decrease at high conversion, as the pH increases above5.5. This system will have less pressure build-up at the back-end of thereaction, after completion of the injection. In other circumstances, itmay be desirable to take advantage of the complete reaction cycle andmodify the reaction so that it is close to completion at the end of theinjection event. In some embodiments, tartaric acid and oxalic acids arepreferred choices due to their lower pKa values.

In some preferred embodiments, the bicarbonate is added as a saturatedsolution to an expansion compartment containing solid acid or solid acidmixed with other components, such as salts, bicarbonate, or otheradditives. In other embodiments, water is added to the piston containingsolid acid, mixed with bicarbonates and other components. In some otherpreferred embodiments, a solution of aqueous bicarbonate is added to asolid composition comprising solid bicarbonate to provide additional CO₂production at the end of the injection. In still other embodiments, thebicarbonate can be present as a wetted, or only partly dissolved solid.Any form of bicarbonate can also be reacted with a dissolved acid. Forexample, in some preferred embodiments, bicarbonate is combined with asolution of citric acid.

When the chemistry is confined to small reaction volumes, i.e., arelatively large amount of reagent is confined to a small volume ofliquid (saturated solutions) in a pressurized system, the process toproduce CO₂(g) becomes considerably more complex. Depending on thecircumstances, important rate limiting steps now become:

-   -   dissolution rate of solid reagents    -   availability and diffusion rate of bicarbonate ions    -   desorption rate of CO₂ from bicarbonate surface    -   release of CO₂ (g) from solution        Depending on the needs of the system, the parameters may be        tuned independently or in concert to minimize overshoot and        maintain a flat pressure profile curve, where the impact of        volume expansion of the chemical reaction chamber does not cause        the pressure to drop and delivery to stall.

To achieve fast delivery of viscous fluids, the availability ofbicarbonate ion can be an important factor. In solution, bicarbonatesalts are in equilibrium with bicarbonate ions, which are the activespecies in the reaction. Bicarbonate ions can be free species orstrongly associated. The concentration of bicarbonate can be controlledby altering solvent polarity—such as adding ethanol to decrease thereaction rate or adding N-methylformamide or N-methylacetamide toincrease the reaction rate; taking advantage of common ion effects; andutilizing relatively high content of bicarbonate above the saturationpoint. The bicarbonate preferably has a solubility in water higher than9 g in 100 mL, more preferably 25 g in 100 mL. In some preferredembodiments, saturated solutions of potassium bicarbonate are added tothe piston containing acids. In other embodiments, water is added to apiston containing solid acids and potassium bicarbonate.

The pressure profile during delivery can be modified by modifying therate of dissolution. For example, the addition of a saturated solutionof potassium bicarbonate to a piston containing solid citric acid andsolid bicarbonate provides first a rapid burst of CO₂ as the dissolvedbicarbonate reacts with acid and second a secondary sustained level ofCO₂ as solid bicarbonate is dissolved and becomes available. Dissolutionrates can be modified by changing the particle size or surface area ofthe powder, employing several different species of bicarbonate or acid,encapsulation with a second component, or changes in the solventquality. By combining powders that have different dissolution rates, thepressure versus time profile can be modified, enabling constant pressurewith time or a burst in the pressure with time. Introduction of acatalyst can be used to the same effect.

The pressure in the piston (reaction chamber) is determined by theconcentration of CO₂ that is released from the solution. Release can befacilitated by introducing methods of agitation or by introducing sitesthat decrease solubility of CO₂ or enhance its nucleation, growth, anddiffusion. Methods of agitation may include introduction of rigidspheres suspended in the piston. Suitable spheres include hollowpolymeric microspheres such as Expancel, polystyrene microspheres, orpolypropylene microspheres. Upon introduction of water or saturatedbicarbonate to the piston, the external flow induces forces and torqueson the spheres, resulting in their rotations with velocity w as well asthey start to move induced by buoyancy force. The flow field generatedby rotation of sphere improves gas diffusion toward surface andfacilitating CO₂ desorption from liquid. The surface of the freelyrotating spheres may also be modified by an active layer, such as bycoating with bicarbonate. Such spheres are initially heavy andunaffected by buoyancy force. However as coating dissolves or reactswith acid, buoyancy will begin to cause spheres to move toward surfaceof liquid. During aforementioned motion the unbalance forces on theparticle promotes spinning, reducing gas transport limitation andincreasing CO₂ desorption from liquid.

In some embodiments, a salt, additive or other nucleating agent is addedto facilitate release of the dissolved gas into the empty volume.Examples of said nucleating agents include crystalline sodium chloride,calcium tartarate, calcium oxalate, and sugar. Release can befacilitated by adding a component that decreases the solubility of thegas. It can also be facilitated by adding a nucleating agent thatfacilitates the nucleation, growth, and release of gas bubbles viaheterogeneous nucleation.

In preferred embodiments, the flow rate versus time is maintainedsubstantially constant, such that the shear rate on the fluid issimilar. For Newtonian fluids, the shear rate is proportional to flowrate and inversely proportional to r³, where r is the radius of theneedle. The change in shear rate can be defined once flow is initiatedafter the first 2 or 3 seconds as [(Flow Rate Max−Flow Rate Min)/FlowRate Min)]·100 for devices where the needle diameter does not change. Inpreferred embodiments, the change in shear rate is less than 50%, morepreferably less than 25%. The fluids may be Newtonian or non-Newtonian.For flow rates typical in subcutaneous delivery through needles withdiameters in the 27 gauge to 31 gauge range, shear rates are on theorder of 1×10⁴ to 1×10⁴ s⁻¹ and non-Newtonian effects could becomeimportant, particularly for proteins.

In some examples described further herein, an injection device using agas-generating chemical reaction was used to displace fluid having aviscosity greater than 70 centipoise (cP) through a 27 gauge thin-wall(TW) needle in less than 10 seconds. A 27 gauge thin-wall needle has anominal outer diameter of 0.016±0.0005 inches, a nominal inner diameterof 0.010±0.001 inches, and a wall thickness of 0.003 inches. Suchresults are expected to also be obtained with needles having largernominal inner diameters.

The selection of the chemical reagent(s) can be based on differentfactors. One factor is the dissolution rate of the reagent, i.e. therate at which the dry powder form of the reagent dissolves in a solvent,such as water. The dissolution rate can be modified by changing theparticle size or surface area of the powder, encapsulating the powderwith a coating that dissolves first, or changes in the solvent quality.Another factor is the desired pressure versus time profile. The pressureversus time profile can be controlled by modifying the kinetics of thereaction. In the simplest case, the kinetics of a given reaction willdepend on factors such as the concentration of the reagents, dependingon the “order” of the chemical reaction, and the temperature. For manyreagents 100, including those in which two dry reagents must be mixed,the kinetics will depend on the rate of dissolution. For example, bycombining powders that have two different dissolution rates, thepressure versus time profile can be modified, enabling constant pressureover time or a profile having a burst in pressure at a specified time.Introduction of a catalyst can be used to the same effect.Alternatively, a delivered volume versus time profile can have aconstant slope. The term “constant” refers to the given profile having alinear upward slope over a time period of at least 2 seconds, with anacceptable deviation in the value of the slope of ±15%.

This ability to tune the chemical reaction allows the devices of thepresent disclosure to accommodate different fluids (with varying volumesand/or viscosities), patient needs, or delivery device designs.Additionally, while the chemical reaction proceeds independently of thegeometry of the reaction chamber, the shape of the reaction chamber canaffect how accumulated pressure acts on the piston.

The target pressure level for providing drug delivery may be determinedby the mechanics of the syringe, the viscosity of the fluid, thediameter of the needle, and the desired delivery time. The targetpressure is achieved by selecting the appropriate amount andstoichiometric ratio of reagent, which determines n (moles of gas),along with the appropriate volume of the reaction chamber. Thesolubility of the gas in any liquid present in the reaction chamber,which will not contribute to the pressure, should also be considered.

If desired, a release agent may be present in the reaction chamber toincrease the rate of fluid delivery. When a solvent, such as water, isused to facilitate diffusion and reaction between molecules, thegenerated gas will have some solubility or stability in the solvent. Therelease agent facilitates release of any dissolved gas into the headspace of the chamber. The release agent decreases the solubility of thegas in the solvent. Exemplary release agents include a nucleating agentthat facilitates the nucleation, growth, and release of gas bubbles viaheterogeneous nucleation. An exemplary release agent is sodium chloride(NaCl). The presence of the release agent can increase the overall rateof many chemical reactions by increasing the dissolution rate, which isoften the rate limiting factor for pressure generation for dry (powder)reagents. The release agent may also be considered to be a catalyst.

In some preferred embodiments, the volume of the reaction chamber is 1to 1.4 cm³ or less, in some preferred embodiments 1 cm³ or less, in someembodiments in the range of 0.5 to 1 or 1.4 cm³. The other components ofthe device can be dimensioned to match the volume of the reactionchamber. A reaction chamber no more than 1 to 1.4 cm³ allows enableschemical-reaction delivery of a high-viscosity fluid with a limitedinjection space or footprint.

FIG. 2 illustrates one exemplary embodiment of a device (here, asyringe) that can be used to deliver a high-viscosity fluid using achemical reaction between reagents to generate a gas. The syringe 400 isdepicted here in a storage state or a non-depressed state in which thechemical reaction has not yet been initiated. The needle is not includedin this illustration. The syringe 400 includes a barrel 410 that isformed from a sidewall 412, and the interior space is divided into threeseparate chambers. Beginning at the top end 402 of the barrel, thesyringe includes a reagent chamber 420, a reaction chamber 430, and afluid chamber 440. The plunger 470 is inserted into an upper end 422 ofthe reagent chamber. A one-way valve 450 is present at a lower end 424of the reagent chamber, forming a radial surface. The one-way valve 450is also present at the upper end 432 of the reaction chamber. Theone-way valve 450 is directed to permit material to exit the reagentchamber 420 and to enter the reaction chamber 430. The lower end 434 ofthe reaction chamber is formed by a piston 460. Finally, the piston 460is present at the upper end 442 of the fluid chamber. The orifice 416 ofthe barrel is at the lower end 444 of the fluid chamber, and at thebottom end 404 of the syringe. It should be noted that the one-way valve450 is fixed in place and cannot move within the barrel 410. Incontrast, the piston 460 can move within the barrel in response topressure. Put another way, the reaction chamber 430 is defined by theone-way valve 450, the barrel sidewall 412, and the piston 460.

The reaction chamber 430 can also be described as having a first end anda second end. The moveable piston 460 is at the first end 434 of thereaction chamber, while the one-way valve 450 is present at the secondend 432 of the reaction chamber. In this illustration, the reactionchamber 430 is directly on one side of the piston 460, and the fluidchamber 440 is directly on the opposite side of the piston.

The reagent chamber 420 contains at least one chemical reagent, asolvent, and/or a release agent. The reaction chamber 430 contains atleast one chemical reagent, a solvent, and/or a release agent. The fluidchamber 440 contains the fluid to be delivered. As depicted here, thereagent chamber 420 contains a solvent 480, the reaction chamber 430contains two different chemical reagents 482, 484 in a dry powder form,and the fluid chamber 440 contains a high-viscosity fluid 486. Again, itshould be noted that this figure is not drawn to scale. The chemicalreagents, as illustrated here, do not fill up the entire volume of thereaction chamber. Instead, a head space 436 is present within thereaction chamber.

In specific embodiments, the reagent chamber contains a bicarbonatewhich has been pre-dissolved in a solvent, and the reaction chambercontains a dry acid powder. It was found that passive mixing of reagentsin the solvent was a problem that would reduce the speed of reaction.Bicarbonate was pre-dissolved, otherwise it was too slow to dissolve andparticipate in the gas generating reaction. In more specificembodiments, potassium bicarbonate was used. It was found that sodiumbicarbonate did not react as quickly. Citrate was used as the dry acidpowder because it was fast-dissolving and fast-reacting. Sodium chloride(NaCl) was included as a dry release agent with the citrate. The sodiumchloride provided nucleation sites to allow the gas to evolve fromsolution more quickly.

Each chamber has a volume, which in the depicted illustration isproportional to the height of the chamber. The reagent chamber 420 has aheight 425, the reaction chamber 430 has a height 435, and the fluidchamber 440 has a height 445. In this non-depressed state, the volume ofthe reaction chamber is sufficient to contain the solvent and the twochemical reagents.

In particular embodiments, the volume of the reaction chamber is 1 cm³or less. The other components of the device can be dimensioned to matchthe volume of the reaction chamber. A reaction chamber no more than 1cm³ allows enables chemical-reaction delivery of a high-viscosity fluidwith a limited injection space or footprint.

In FIG. 3, the plunger 470 has been depressed, i.e. the syringe is in adepressed state. This action causes the one-way valve 450 to be opened,and the solvent 480 enters into the reaction chamber 430 and dissolvesthe two chemical reagents (illustrated now as bubbles in the solvent).After the plunger 470 is depressed and no further pressure is beingexerted on the one-way valve, the one-way valve 450 closes (this figureshows the valve in an open state). In particular embodiments, the barrelsidewall 412 at the lower end 424 of the reagent chamber may containgrooves 414 or is otherwise shaped to capture the plunger 470. Putanother way, the plunger 470 cooperates with the lower end 424 of thereagent chamber 420 to lock the plunger in place after being depressed.

In FIG. 4, the dissolution of the two chemical reagents in the solventhas resulted in the generation of a gas 488 as a byproduct of thechemical reaction. As the amount of gas increases, the pressure exertedon the piston 460 increases until, after reaching a threshold value, thepiston 460 moves downward towards the bottom end 404 of the syringe (asindicated by the arrow). This causes the volume of the reaction chamber430 to increase, and the volume of the fluid chamber 440 to decrease.This results in the high-viscosity fluid 486 in the fluid chamber beingdispensed through the orifice. Put another way, the combined volume ofthe reaction chamber 430 and the fluid chamber remains constant, but thevolume ratio of reaction chamber to fluid chamber 440 will increase asgas is generated in the reaction chamber. Note that the one-way valve450 does not permit the gas 488 to escape from the reaction chamber intothe reagent chamber.

The syringe can provide consistent force when the following elements areproperly controlled: (i) the particle size of the dry powder reagent;(ii) the solubility of the reagents; (iii) the mass of the reagents andthe quantity of release agent; and (iv) the shape configuration of thechambers for consistent filling and packaging.

FIG. 5 illustrates another variation of a device 700 that uses achemical reaction between reagents to generate gas. This illustration isin a storage state. Whereas the barrel of FIG. 2 is shown as being madefrom an integral sidewall, the barrel in the device of FIG. 5 is made ofseveral shorter pieces. This construction can simplify manufacturing andfilling of the various chambers of the overall device. Another largedifference in this variation is that the piston 760 is made up of threedifferent parts: a push surface 762, a rod 764, and a stopper 766, asexplained further herein.

Beginning at the top of FIG. 5, the reagent chamber 720 is made from afirst piece 726 that has a first sidewall 728 to define the sides of thereagent chamber. The plunger 770 is inserted in the upper end 722 of thepiece to seal that end. The first piece 720 can then be turned upsidedown to fill the reagent chamber 720 with the solvent 780.

A second piece 756 containing the one-way valve 750 can then be joinedto the lower end 724 of the first piece to seal the reagent chamber 720.A second sidewall 758 surrounds the one-way valve. The lower end 724 ofthe first piece and the upper end 752 of the second piece can be joinedusing known means, such as screw threads (e.g. a Luer lock). Asillustrated here, the lower end of the first piece would have internalthreads, while the upper end of the second piece would have the externalthreads.

The third piece 736 is used to form the reaction chamber 730, and isalso formed from a third sidewall 738. The push surface 762 of thepiston is located within the third sidewall 738. After placing thechemical reagents, solvent, and/or release agent upon the push surface,the lower end 754 of the second piece and the upper end 732 of the thirdpiece are joined together. Two reagents 782, 784 are depicted here. Therod 764 of the piston extends down from the push surface 762.

Finally, the fourth piece 746 is used to form the fluid chamber 740.This fourth piece is formed from a fourth sidewall 748 and a conicalwall 749 that tapers to form the orifice 716 from which fluid will beexpelled. The orifice is located at the lower end 744 of the fluidchamber. The fluid chamber can be filled with the fluid to be delivered,and the stopper 766 can then be placed in the fluid chamber. As seenhere, the stopper 766 may include a vent hole 767 so that air can escapefrom the fluid chamber as the stopper is being pushed down to thesurface of the fluid 786 to prevent air from being trapped in the fluidchamber. A cap 768 attached to the lower end of the piston rod 764 canbe used to cover the vent hole 767. Alternatively, the lower end of thepiston rod can be inserted into the vent hole. The lower end 734 of thethird piece and the upper end 742 of the fourth piece are then joinedtogether.

As previously noted, the piston 760 in this variation is formed from thepush surface 762, the rod 764, and the stopper 766 being connectedtogether. An empty volume 790 is thus present between the reactionchamber 730 and the fluid chamber 740. The size of this empty volume canbe varied as desired. For example, it may be useful to make the overalldevice longer so that it can be more easily grasped by the user.Otherwise, this variation operates in the same manner as described abovewith regards to FIGS. 2-4. The push surface portion of the piston actsin the reaction chamber, and the stopper portion of the piston acts inthe fluid chamber. It should also be noted that the push surface, rod,stopper, and optional cap can be one integral piece, or can be separatepieces.

FIG. 6 illustrates an exemplary embodiment of a device (again, asyringe) that can be used to deliver a high-viscosity fluid using achemical reaction initiated by heat to generate a gas. Again, thesyringe 800 is depicted here in a storage state.

The barrel 810 is formed from a sidewall 812 and the interior space isdivided into two separate chambers, a reaction chamber 830 and a fluidchamber 840. The reaction chamber 830 is present at an upper end 802 ofthe syringe. The upper end 832 of the reaction chamber is formed by aradial wall 838. Located within the reaction chamber is a thermal source850 that can be used for heating. The thermal source 850 may be locatedon the radial wall 838 or, as depicted here, on the barrel sidewall 812.

The lower end 834 of the reaction chamber is formed by a piston 860. Thereaction chamber 830 is defined by the radial wall 838, the barrelsidewall 812, and the piston 860. The piston 860 is also present at theupper end 842 of the fluid chamber. The orifice 816 of the barrel is atthe lower end 844 of the fluid chamber, i.e. at the lower end 804 of thesyringe. Again, only the piston 860 portion of the reaction chamber canmove within the barrel 810 in response to pressure. The radial wall 838is fixed in place, and is solid so that gas cannot pass through.

The reaction chamber contains a chemical reagent 882. For example, thechemical reagent can be 2,2′-azobisisobutyronitrile. A head space 836may be present in the reaction chamber. The fluid chamber 840 contains afluid 886.

An activation trigger 852 is present on the syringe, which can be forexample on top near the finger flange 815 or on the external surface 816of the barrel sidewall. When activated, the thermal source 850 generatesheat. The thermal source can be, for example, an infrared light emittingdiode (LED). The chemical reagent 882 is sensitive to heat, andgenerates a gas (here, N2). The pressure generated by the gas causes thepiston 860 to move, expelling the high-viscosity fluid 886 in the fluidchamber 840.

It should be noted again that the piston may alternatively be the pushsurface, rod, and stopper version described in FIG. 5. This version maybe appropriate here as well.

In an alternative embodiment, of a device that can be used to deliver ahigh-viscosity fluid using a chemical reaction initiated by light togenerate a gas. This embodiment is almost identical to the versiondescribed in FIG. 6, except that the thermal source is now replaced by alight source 850 which can illuminate the reaction chamber 830. Thechemical reagent 884 here is sensitive to light, and generates a gasupon exposure to light. For example, the chemical reagent may be silverchloride (AgCl). The pressure generated by the gas causes the piston tomove, expelling the high-viscosity fluid in the fluid chamber. Thepiston version of FIG. 5 can also be used here if desired.

Any suitable chemical reagent or reagents can be used to generate a gas.For example, bicarbonate will react with acid to form carbon dioxide.Sodium, potassium, and ammonium bicarbonate are examples of suitablebicarbonates. Suitable acids could include acetic acid, citric acid,potassium bitartrate, disodium pyrophosphate, or calcium dihydrogenphosphate. Any gas can be generated by the chemical reaction, such ascarbon dioxide, nitrogen gas, oxygen gas, chlorine gas, etc. Desirably,the generated gas is inert and non-flammable. Metal carbonates, such ascopper carbonate or calcium carbonate, can be decomposed thermally toproduce CO₂ and the corresponding metal oxide. As another example,2,2′-azobisisobutyronitrile (AIBN) can be heated to generate nitrogengas. As yet another example, the reaction of certain enzymes (e.g.yeast) with sugar produces CO₂. Some substances readily sublime, goingfrom solid to gas. Such substances include but are not limited tonaphthalene and iodine. Hydrogen peroxide can be decomposed withcatalysts such as enzymes (e.g. catalase) or manganese dioxide toproduce oxygen gas.

It is contemplated that the high-viscosity fluid to be dispensed usingthe devices of the present disclosure can be a solution, dispersion,suspension, emulsion, etc. The high-viscosity formulation may contain aprotein, such as a monoclonal antibody or some other protein which istherapeutically useful. The protein may have a concentration of fromabout 150 mg/ml to about 500 mg/ml. The high-viscosity fluid may have anabsolute viscosity of from about 5 centipoise to about 1000 centipoise.In other embodiments, the high-viscosity fluid has an absolute viscosityof at least 40 centipoise, or at least 60 centipoise. The high-viscosityfluid may further contain a solvent or non-solvent, such as water,perfluoroalkane solvent, safflower oil, or benzyl benzoate.

FIG. 7 and FIG. 8 are different views of the first exemplary embodimentof an injection device (here, a syringe) that can be used to deliver ahigh-viscosity fluid using a chemical reaction between reagents togenerate a gas. The syringe 300 is depicted here in a storage state or anon-depressed state in which the chemical reaction has not yet beeninitiated. FIG. 7 is a side cross-sectional view, and FIG. 8 is aperspective view of the engine of the syringe.

The syringe 300 includes a barrel 310 whose interior space is dividedinto three separate chambers.

Beginning at the top end 302 of the barrel, the syringe includes anupper chamber 320, a lower chamber 330, and a fluid chamber 340. Thesethree chambers are coaxial, and are depicted here as having acylindrical shape. The lower chamber may also be considered a reactionchamber.

The plunger 370 is inserted into an upper end 322 of the upper chamber,and the stopper 372 of the plunger travels through only the upperchamber. A one-way valve 350 is present at a lower end 324 of the upperchamber, forming a radial surface. The one-way valve 350 is also presentat the upper end 332 of the lower chamber. The one-way valve 350 isdirected to permit material to exit the upper chamber 320 and to enterthe lower chamber 330. A piston 360 is present at the lower end 334 ofthe lower chamber. The piston 360 is also present at the upper end 342of the fluid chamber. As illustrated here, the piston is formed of atleast two pieces, a push surface 362 that is at the lower end of thelower chamber and a head 366 at the upper end of the fluid chamber. Theneedle 305 is at the lower end 344 of the fluid chamber, and at thebottom end 304 of the syringe. It should be noted that the one-way valve350 is fixed in place and cannot move within the barrel 310, or in otherwords is stationary relative to the barrel. In contrast, the piston 360can move within the barrel in response to pressure. Put another way, thelower chamber 330 is defined by the one-way valve 350, the continuoussidewall 312 of the barrel, and the piston 360.

The lower chamber 330 can also be described as having a first end and asecond end. The moveable piston 360 is at the first end 334 of the lowerchamber, while the one-way valve 350 is present at the second end 332 ofthe lower chamber. In this illustration, the lower chamber 330 isdirectly on one side of the piston 360, and the fluid chamber 340 isdirectly on the opposite side of the piston.

As previously noted, the piston 360 is formed from at least the pushsurface 362 and the head 366. These two pieces can be connected togetherphysically, for example with a rod (not shown) that has the push surfaceand the head on opposite ends. Alternatively, it is also contemplatedthat an incompressible gas could be located between the push surface andthe head. An empty volume 307 would thus be present between the lowerchamber 330 and the fluid chamber 340. The size of this empty volumecould be varied as desired. For example, it may be useful to make theoverall device longer so that it can be more easily grasped by the user.Alternately, as illustrated in another embodiment in FIG. 9 and FIG. 10further herein, the piston may use a balloon that acts as the pushsurface and acts upon the head 366. As yet another variation, the pistonmay be a single piece, with the push surface being on one side of thesingle piece and the head being on the other side of the single piece.

The upper chamber 320 contains at least one chemical reagent or asolvent. The lower chamber 330 contains at least one chemical reagent ora solvent. The fluid chamber 340 contains the fluid to be delivered. Itis generally contemplated that dry reagents will be placed in the lowerchamber, and a wet reagent (i.e. solvent) will be placed in the upperchamber. As depicted here, the upper chamber 320 would contain asolvent, the lower chamber 330 would contain two different chemicalreagents in a dry powder form, and the fluid chamber 340 would contain ahigh-viscosity fluid. The reagent(s) in either chamber may beencapsulated for easier handling during manufacturing. Each chamber hasa volume, which in the depicted illustration is proportional to theheight of the chamber. In this non-depressed state, the volume of thelower chamber is sufficient to contain the solvent and the two chemicalreagents.

When the plunger in the syringe of FIG. 7 and FIG. 8 is depressed, theadditional pressure causes the one-way valve 350 to open, and thesolvent in the upper chamber 320 enters into the lower chamber 330 anddissolves the two chemical reagents. After the plunger 370 issufficiently depressed and no further pressure is being exerted on theone-way valve, the one-way valve 350 closes. As illustrated here, theplunger includes a thumbrest 376 and a pressure lock 378 on the shaft374 which is proximate to the thumbrest. The pressure lock cooperateswith an upper surface 326 of the upper chamber to lock the plunger inplace. The two chemical reagents may react with each other in thesolvent to generate gas in the lower chamber. As the amount of gasincreases, the pressure exerted on the push surface 362 of the piston360 increases until, after reaching a threshold value, the piston 360moves downward towards the bottom end 304 of the syringe. This causesthe volume of the lower chamber 330 to increase, and the volume of thefluid chamber 340 to decrease. This results in the high-viscosity fluidin the fluid chamber being dispensed through the orifice (by the head366). Put another way, the combined volume of the lower chamber 330 andthe fluid chamber remains constant, but the volume ratio of lowerchamber to fluid chamber 340 will increase as gas is generated in thereaction chamber. Note that the one-way valve 350 does not permit thegas to escape from the lower chamber into the upper chamber. Also, thepressure lock 378 on the plunger permits the stopper 372 to act as asecondary backup to the one-way valve 350, and also prevents the plungerfrom being pushed up and out of the upper chamber.

In some embodiments, the upper chamber contains a bicarbonate which hasbeen pre-dissolved in a solvent, and the lower chamber contains a dryacid powder. Passive mixing of reagents in the solvent, i.e. combiningboth dry powders into the reaction chamber and adding water, reduces thespeed of reaction. One reagent may be predissolved. For example,bicarbonate may be pre-dissolved. In more specific embodiments,potassium bicarbonate is recommended. Sodium bicarbonate does not reactas quickly; therefore CO₂ production and injection rates are slower.Citric acid is a preferred dry acid powder because it dissolves well andis fast-reacting, as well as safe. Sodium chloride (NaCl) is included asa dry release agent with the citric acid. The sodium chloride providednucleation sites and changed the ionic strength to allow the gas toevolve from solution more quickly.

It should be noted that the upper chamber 320, the lower chamber 330,and the fluid chamber 340 are depicted here as being made from separatepieces that are joined together to form the syringe 300. The pieces canbe joined together using methods known in the art. For example, theupper chamber is depicted here as being formed from a sidewall 325having a closed upper end 322 with a port 327 for the plunger. Thestopper 372 of the plunger is connected to the shaft 374. The one-wayvalve 350 is a separate piece which is inserted into the open lower end324 of the upper chamber. The lower chamber is depicted here as beingformed from a sidewall 335 having an open upper end 332 and an openlower end 334. The upper end of the lower chamber and the lower end ofthe upper chamber cooperate to lock together and fix the one-way valvein place. Here, the locking mechanism is a snap fit arrangement, withthe upper end of the lower chamber having the cantilever snap 380 thatincludes an angled surface and a stop surface. The lower end of theupper chamber has the latch 382 that engages the cantilever snap.Similarly, the lower chamber and the fluid chamber are fitted togetherwith a ring-shaped seal.

FIG. 9 and FIG. 10 are different views of an exemplary embodiment of aninjection device of the present disclosure. The syringe 500 is depictedhere in a storage state or a non-depressed state in which the chemicalreaction has not yet been initiated. FIG. 9 is a side cross-sectionalview, and FIG. 10 is a perspective view of the engine of the syringe.

Again, the syringe includes a barrel 510 whose interior space is dividedinto three separate chambers. Beginning at the top end 502 of thebarrel, the syringe includes an upper chamber 520, a lower chamber 530,and a fluid chamber 540. These three chambers are coaxial, and aredepicted here as having a cylindrical shape. The lower chamber 530 mayalso be considered a reaction chamber.

In this embodiment, the upper chamber 520 is a separate piece locatedwithin the barrel 510. The barrel is illustrated here as an outersidewall 512 that surrounds the upper chamber. The upper chamber 520 isillustrated here with an inner sidewall 525 and a top wall 527. A shaft574 and a thumbrest I button 576 extend from the top wall 527 of theupper chamber in the direction away from the barrel. Thus, the upperchamber 520 could also be considered as forming the lower end of aplunger 570. The lower end 524 of the upper chamber is closed off with aseal 528, i.e. a membrane or barrier such that the upper chamber has anenclosed volume. It should be noted that the inner sidewall 525 of theupper chamber travels freely within the outer sidewall 512 of thebarrel. The upper chamber moves axially relative to the lower chamber.

The lower chamber 530 has a port 537 at its upper end 532. A ring 580 ofteeth is also present at the upper end 532. Here, the teeth surround theport. Each tooth 582 is illustrated here as having a triangular shape,with a vertex oriented towards the seal 528 of the upper chamber, andeach tooth is angled inwards towards the axis of the syringe. The term“tooth” is used here generally to refer to any shape that can puncturethe seal of the upper chamber.

A piston 560 is present at the lower end 534 of the lower chamber 530.The piston 560 is also present at the upper end 542 of the fluid chamber540. Here, the piston 560 includes the head 566 and a balloon 568 withinthe lower chamber that communicates with the port 537 in the upper end.Put another way, the balloon acts as a push surface for moving the head.The head 566 may be described as being below or downstream of theballoon 568, or alternatively the balloon 568 can be described as beinglocated between the head 566 and the port 537. The needle 505 is at thelower end 544 of the fluid chamber, and at the bottom end 504 of thesyringe. The balloon is made from a suitably non-reactive material.

The top end 502 of the barrel (i.e. the sidewall) includes a pressurelock 518 that cooperates with the top surface 526 of the upper chamberto lock the upper chamber 520 in place when moved sufficiently towardsthe lower chamber 530. The upper chamber 520 is illustrated hereextending out of the outer sidewall 512. The top end 526 of the outersidewall is shaped to act as the cantilever snap, and the top surface526 of the upper chamber acts as the latch.

Alternatively, the top end of the device may be formed as depicted inFIG. 8, with the pressure lock on the shaft proximate to the thumbrestand cooperating with the top end of the device.

As previously described, it is generally contemplated that dry reagentswill be placed in the lower chamber 530, and a wet reagent (i.e.solvent) will be placed in the upper chamber 520. Again, the reagent(s)in either chamber may be encapsulated for easier handling duringmanufacturing. More specifically, it is contemplated that the reagentsin the lower chamber would be located within the balloon 568.

During operation of the syringe of FIG. 9 and FIG. 10, pushing thebutton 576 downwards causes the upper chamber 520 to move into thebarrel towards the ring 580 of teeth. The pressure of the upper chamberagainst the ring of teeth causes the seal 528 to break, releasing thecontents of the upper chamber into the lower chamber 530. Here, it iscontemplated that the gas-generating reaction occurs within the balloon568. The increased gas pressure causes the balloon to inflate (i.e.lengthen). This pushes the head 566 towards the bottom end 504 of thesyringe (note the upper chamber will not be pushed out of the barrel dueto the pressure lock). This again causes the volume of the lower chamber530 to increase, and the volume of the fluid chamber 540 to decrease,i.e. the volume ratio of lower chamber to fluid chamber to increase.

There is an empty volume 507 present between the balloon 568 and thehead 566. An incompressible gas could be located in this empty volume.The size of this empty volume can be varied as desired, for example tomake the overall device longer.

Again, the upper chamber 520, the lower chamber 530, and the fluidchamber 540 can be made from separate pieces that are joined together toform the syringe. It should be noted that FIG. 10 is made from fivepieces (590, 592, 594, 596, and 598), with the additional pieces beingdue to the addition of the balloon in the lower chamber and to the upperchamber being separate from the outer sidewall. However, this embodimentcould still be made from fewer pieces as in FIG. 8. For example, theballoon could be located close to the ring of teeth.

FIG. 11, FIG. 12, and FIG. 13 are different views of a third exemplaryembodiment of an injection device of the present disclosure. In thisembodiment, the mixing of the chemical reagents is initiated by pullingthe plunger handle away from the barrel, rather than towards the barrelas in the embodiments of FIGS. 7-10. FIG. 11 is a side cross-sectionalview of the syringe in a storage state. FIG. 12 is a perspective view ofthe engine of the syringe in a storage state. FIG. 13 is a perspectiveview of the engine of the syringe in its operating state, i.e. when thehandle is pulled upwards away from the barrel of the syringe.

The syringe 700′ includes a barrel 710′ whose interior space is dividedinto three separate chambers. Beginning at the top end 702′ of thebarrel, the syringe includes an upper chamber 720′, a lower chamber730′, and a fluid chamber 740′. These three chambers are coaxial, andare depicted here as having a cylindrical shape. The lower chamber mayalso be considered a reaction chamber.

In this embodiment, the plunger 770′ is inserted into an upper end 722′of the upper chamber. In the storage state, the shaft 774′ runs throughthe upper chamber from the lower end 724′ to the upper end 722′ andthrough the upper surface 726′ of the upper chamber. A seal 728′ ispresent at the top end where the shaft exits the upper chamber. Thethumbrest 776′ at the upper end of the shaft is outside of the upperchamber. The stopper 772′ at the lower end of the shaft cooperates witha seat 716′ within the barrel such that the upper chamber has anenclosed volume. For example, the top surface of the stopper may have alarger diameter than the bottom surface of the stopper. The seat 716′may be considered as being at the lower end 724′ of the upper chamber,and also as being at the upper end 732′ of the lower chamber.

A piston 760′ is present at the lower end 734′ of the lower chamber. Thepiston 760′ is also present at the upper end 742′ of the fluid chamber740′. As illustrated here, the piston 760′ is formed of at least twopieces, a push surface 762′ and a head 766′. An empty volume 707′ can bepresent. Other aspects of this piston are similar to that described inFIG. 8. Again, the piston can move within the barrel in response topressure. The lower chamber 730′ can also be described as being definedby the seat 716, the continuous sidewall 712′ of the barrel, and thepiston 760′. The needle 705′ is at the lower end 744′ of the fluidchamber, and at the bottom end 704′ of the syringe.

During operation of the syringe of FIGS. 11-13, it is generallycontemplated that dry reagents will be placed in the lower chamber 730′,and a wet reagent (i.e. solvent) will be placed in the upper chamber720′, as previously described. Referring now to FIG. 11, pulling theplunger 770′ upwards (i.e. away from the barrel) causes the stopper 772′to separate from the seat 716′. This creates fluid communication betweenthe upper chamber 720′ and the lower chamber 730′. The reagent in theupper chamber travels around the stopper into the lower chamber(reference number 717′). The gas-generating reaction then occurs in thelower chamber 730′. The gas pressure pushes the piston 760′ towards thebottom end 704′ of the syringe. In other words, the volume of the lowerchamber increases, and the volume of the fluid chamber decreases, i.e.the volume ratio of lower chamber to fluid chamber increases. Oneadditional advantage to this embodiment is that once the reagents begingenerating gas, the pressure created will continue to push the plunger710′ further out of the upper chamber, helping to push more reagent outof the upper chamber 720′ into the lower chamber 730′, furthering thegeneration of gas.

Referring to FIG. 12, the barrel 710′ is depicted as being made up ofthree different pieces 790′, 792′, 794′. A seal 738′ is also locatedbetween the pieces that make up the lower chamber and the fluid chamber.

FIG. 14 and FIG. 15 are cross-sectional views of one aspect of anotherexemplary embodiment of the injection device of the present disclosure.In this embodiment, the liquid reagent (i.e. the solvent) isencapsulated in a capsule is broken when a button is pressed. FIG. 14shows this engine before the button is pressed. FIG. 15 shows the engineafter the button is pressed.

Referring first to FIG. 14, the top end 1002 of the syringe 1000 isshown. A reaction chamber 1030 contains a capsule 1038 and dryreagent(s) 1039. Here, the capsule rests on a ledge 1031 above the dryreagent(s). A push surface 1062 of a piston 1060 is present at the lowerend of the reaction chamber. The head 1066 of the piston is alsovisible, and is at the upper end 1042 of the fluid chamber 1040. Abutton/plunger 1070 is located above the capsule. A seal 1026 may bepresent between the button 1070 and the capsule 1038. The barrelcontains a safety snap 1019 to prevent the button from falling out ofthe end of the barrel.

If desired, the portion of the reaction chamber containing the capsulecould be considered an upper chamber, and the portion of the reactionchamber containing the dry reagent(s) could be considered a lowerchamber.

Referring now to FIG. 15, when the button 1070 is pushed, the capsule1038 is broken, causing the solvent and the dry reagent(s) to mix. Thisgenerates a gas that pushes the piston 1060 downward and ejects fluidfrom the fluid chamber 1040. Pushing the button subsequently engages apressure lock 1018 that prevents the button from being pushed upwards bythe gas pressure.

The embodiments of the figures described above have been illustrated asauto-injectors. Auto-injectors are typically held in the user's hand,have a cylindrical form factor, and have a relatively quick injectiontime of one second to 30 seconds. It should be noted that the conceptsembodied in the above-described figures could also be applied to othertypes of injection devices, such as patch pumps. Generally, a patch pumphas a flatter form factor compared to a syringe, and also has thedelivery time is typically greater than 30 seconds. Advantages to usinga chemical gas-generating reaction in a patch pump include the smallvolume required, flexibility in the form/shape, and the ability tocontrol the delivery rate.

FIG. 16 is an illustration of a typical bolus injector 1200. The bolusinjector includes a reaction chamber 1230 and a fluid chamber 1240located within a housing 1280. As shown here, the reaction chamber andthe fluid chamber are located side-by-side, though this can vary asdesired. The reaction chamber 1230 is formed from a sidewall 1235. Thefluid chamber 1240 is also formed from a sidewall 1245. The reactionchamber and the fluid chamber are fluidly connected by a passage 1208 ata first end 1202 of the device. The fluid chamber 1240 includes anoutlet 1246 that is connected to a needle 1205 located at oppositesecond end 1204 of the housing. The needle 1205 extends from the bottom1206 of the housing.

The reaction chamber is divided into a first compartment and a secondcompartment by a barrier (not visible). In this regard, the firstcompartment is analogous to the lower chamber, and the second chamber isanalogous to the upper chamber previously described.

The reaction chamber can be considered as an engine that causes fluid inthe fluid chamber to be ejected. In this regard, it is contemplated thata gas-generating chemical reaction can be initiated by breaking the sealbetween the first compartment and the second compartment. The barriercould be broken, for example, by bending or snapping the patch pumphousing, or by pushing at a designated location on the housing. Thiscauses the reagents to mix. Because the desired delivery time is longer,the speed at which the chemicals are mixed is not as great a concern.The pressure builds up and can act on a piston (not visible) in thefluid chamber, causing fluid to exit through the outlet. It iscontemplated that the volume of the reaction chamber and the fluidchamber do not change significantly in this embodiment.

FIG. 17 and FIG. 18 are perspective see-through views of anotherexemplary embodiment of a patch pump. In this embodiment, the reactionchamber/engine 1230 is located on top of the fluid chamber 1240. Theneedle 1205 extends from the bottom 1206 of the housing 1280. In thisembodiment, the reaction chamber 1230 includes a flexible wall 1235. Thefluid chamber 1240 also includes a flexible sidewall 1245. The flexiblewall of the reaction chamber is proximate to the flexible sidewall ofthe fluid chamber. The reaction chamber and the fluid chamber are notfluidly connected to each other in this embodiment. Instead, it iscontemplated that as gas is generated in the reaction chamber, thereaction chamber will expand in volume. The flexible wall 1235 of thereaction chamber will compress the flexible sidewall 1245 of the fluidchamber, causing fluid in the fluid chamber to exit through the outlet1246. Put another way, the volume ratio of reaction chamber to fluidchamber increases over time as the reaction chamber inflates and thefluid chamber dispenses fluid. It should be noted that a relativelyconstant volume is required in this embodiment, so that the increasingvolume of the reaction chamber causes compression of the fluid chamber.This can be accomplished, for example, by including a rigid backing onthe opposite side of the reaction chamber from the flexible wall, or bymaking the housing from a relatively rigid material.

FIG. 19 illustrates another exemplary embodiment of a device (here, asyringe) that can be used to deliver a high-viscosity fluid using achemical reaction between reagents to generate a gas. The syringe 1300is depicted here in a storage state or a non-depressed state in whichthe chemical reaction has not yet been initiated. The needle is notincluded in this illustration.

The syringe 1300 includes a barrel 1310 whose interior space is dividedinto three separate chambers. Beginning at the top end 1302 of thebarrel, the syringe includes a reagent chamber 1320, a reaction chamber1330, and a fluid chamber 1340. These three chambers are coaxial, andare depicted here as having a cylindrical shape. In this embodiment, thebarrel of the syringe is formed from two different pieces. The firstpiece 1380 includes a sidewall 1312 that forms the reaction chamber andprovides a space 1313 for the reagent chamber. The sidewall is open atthe top end 1302 for a push button described further herein. The fluidchamber is made from a second piece 1390 which can be attached to thefirst piece.

The sidewall 1312 of the first piece includes an interior radial surface1314 that divides the first piece into an upper space 1313 and thereaction chamber 1330. The reaction chamber has a smaller inner diameter1325 compared to the inner diameter 1315 of the upper space.

The reagent chamber is located in a separate push button member 1350that is located within the upper space 1313 of the first piece andextends through the top end 1302 of the barrel. As illustrated here, thepush button member is formed from a sidewall 1352 which is closed at theouter end 1351 by a contact surface 1354, and which forms an interiorvolume into which reagent is placed (i.e. the reagent chamber). Asealing member 1356 (shown here as an 0-ring) is proximate a centralportion on the exterior surface 1355 of the sidewall, and engages thesidewall 1312 in the upper space. The inner end 1353 of the sidewallincludes a lip 1358 extending outwards from the sidewall. The lipengages an interior stop surface 1316 on the barrel. The reagent chamberis depicted as containing a solvent 1306 in which bicarbonate isdissolved.

A plunger 1370 is located between the reagent chamber 1320 and thereaction chamber 1330. The plunger 1370 is located at the inner end 1324of the reagent chamber. The plunger includes a central body 1372 havinglugs 1374 extending radially therefrom (here shown as four lugs, thoughthe number can vary). The lugs also engage the lip 1358 of the pushbutton member when the syringe is in its storage state. The lugs areshaped with an angular surface 1376, such that the plunger 1370 rotateswhen the push button member 1350 is depressed. An inner end 1373 of thecentral body includes a sealing member 1378 (shown here as an O-ring)which engages the sidewall in the reaction chamber.

The reaction chamber 1330 includes a top end 1332 and a bottom end 1334.Another interior radial surface 1336 is located at a central location inthe reaction chamber, separating the reaction chamber into a mixingchamber 1335 and an arm/fitting 1333, with the mixing chamber 1335 beingproximate the reagent chamber 1320 or the top end 1332. An orifice 1331within the interior radial surface leads to the arm fitting 1333 whichengages the second piece 1390 containing the fluid chamber 1340. Thepiston 1360 is located at the bottom end of the reaction chamber, i.e.at the end of the arm 1333. Located within the reaction chamber is a dryreagent 1308. Here, the dry reagent is citrate, and is in the form of atablet. The dry reagent is depicted here as being located upon theinterior radial surface, i.e. in the mixing chamber. A gas-permeable Iliquid-solid impermeable filter 1337 may be present across the orifice.The filter keeps any dry solid reagent and a liquid inside the mixingchamber to improve mixing.

In addition, a compression spring 1395 is located within the mixingchamber, extending from the interior radial surface 1336 to the innerend 1373 of the plunger. A compression spring stores energy whencompressed (i.e. is longer when no load is applied to it). Because thepush button member 1350 and the plunger 1370 are fixed in place, thecompression spring 1395 is compressed in the storage state. It should benoted that here, the spring surrounds the dry reagent. It is alsocontemplated, in alternate embodiments, that the dry reagent is attachedto the inner end 1373 of the plunger.

Finally, the piston 1360 is also present at the upper end 1342 of thefluid chamber. Again, the piston 1360 can move within the barrel inresponse to pressure generated in the reaction chamber. The piston canalso be described as having a push surface 1362 and a stopper 1364.

The sealing member 1378 of the plunger separates the liquid reagent inthe reagent chamber 1320 from the dry reagent in the reaction chamber1330. While liquid 1306 is illustrated as being present in the pushbutton member, it is also possible that liquid is present in the barrelin the upper space 1313 around the plunger.

When the push button member 1350 is depressed (down to the interiorradial surface 1316), the plunger 1370 is rotated. This causes the lugs1374 of the plunger to disengage from the lip 1358 of the push buttonmember. In addition, it is contemplated that the push button member,once depressed, cannot be retracted from the barrel. This can be done,for example, using a stop surface near the outer end of the barrel (notshown).

When the plunger 1370 is no longer held in place by the push buttonmember, the compression spring extends and pushes the plunger 1370 intothe push button member 1350. It is contemplated that the compressionspring is sized so that the plunger travels completely through the pushbutton member, but will not push through the contact surface 1354 of thepush button member. The liquid 1306 present in the reagent chamber fallsinto the reaction chamber and contacts the dry reagent 1308. Themovement of the plunger into the push button member is intended to causecomplete emptying of the contents of the reagent chamber into thereaction chamber. This mechanism can also provide forceful mixing of thewet reagent with the dry reagent, either induced by the spring action,initial chemical action, or both.

In some alternate embodiments, the spring also pushes at least some ofthe dry reagent into the reagent chamber (i.e. the interior volume ofthe push button member). For example, the dry reagent could be attachedto the inner end 1373 of the plunger, and driven upwards by the spring.

FIG. 20 is a bottom view illustrating the interior of the push buttonmember. As seen here, the interior surface 1357 of the sidewall formingthe push button member includes four channels 1359 through which thelugs of the plunger can travel. FIG. 21 is a top view of the plunger1370, showing the central body 1372 and the lugs 1374, which can travelin the channels of the push button member. Comparing these two figures,the outer circle of FIG. 20 is the lip 1358 of the push button memberand has an outer diameter 1361. The inner diameter 1363 of the pushbutton member is interrupted by the four channels. The dotted circleindicates the outer diameter 1365 of the sidewall exterior surface 1355.The central body of the plunger has a diameter 1375 which is less thanthe inner diameter 1363 of the push button member, with the lugs fittinginto the channels. This permits the plunger to push the liquid in thepush button member out and around the central body. It should be notedthat the channels do not need to be straight, as illustrated here. Forexample, the channels may be angled to one side, i.e. twist in a helicalmanner. This might be desirable to add turbulence to the liquid reagentand improve mixing.

The combination of the solvent with bicarbonate and the citrate in thereaction chamber 1330 causes gas 1309 to be generated. It should benoted that due to the movement of the plunger, the reagent chamber couldnow be considered to be part of the reaction chamber. In addition, itshould be noted that the dry reagent 1308 in FIG. 19 could be consideredas restricting access to the orifice 1331. Upon dissolution, the orificeis clear and gas can enter the bottom end 1334 of the reaction chamber.

Once a threshold pressure is reached, the piston 1360 travels throughthe fluid chamber 1340, ejecting fluid from the syringe. The needle 1305of the syringe is visible in this figure.

In some alternate contemplated embodiments, the diameter of the plungerincluding the lugs is less than the inner diameter 1363 of the pushbutton member. In other words, channels are not needed on the innersidewall of the push button member. In such embodiments, the barrelsidewall would provide a surface that holds the plunger in place untilthe push button is depressed to rotate the plunger. The shape andmovement of the plunger would then cause turbulence in the liquid as thewet reagent flowed past the lugs into the reaction chamber. It is alsocontemplated that a stem could be attached to the plunger that extendsinto the reagent chamber, or put another way, the stem is attached tothe outer end of the plunger. The stem may be shaped to cause turbulenceand improve mixing.

To speed gas generation in a chemical engine, a conduit comprisingapertures such as that shown in FIG. 37 can be utilized. In conduit3700, flow 3703 is directed into the conduit at an inlet and then flowsout through plural apertures 3705 (preferably 5 or more apertures) intoa reaction chamber. The conduit-with-apertures configuration isespecially advantageous where the reaction chamber comprises a powderwhere flow from apertures directly contacts the powder. For example, anacid solution (preferably a citric acid solution) flows through theconduit and out from the apertures where it contacts and agitates solidbicarbonate particles. In some preferred embodiments, a plunger (such asa spring-activated plunger) forces a liquid solution through theconduit. In some cases, the conduit contains a solid (preferably solidbicarbonate) which at least partly dissolves as the solution flowsthrough the conduit; this may offer the dual advantage of both enhanceddissolution as well the creation of gas bubbles in the conduit thatenhance mixing as they pass through the apertures and into the reactionchamber. Any of the devices described herein for adding a solution intoa reaction chamber can be used to direct fluid down this conduit.

It is also contemplated that the speed of the injection could beadjusted by the user. One way of doing this would be to control thespeed at which the dry reagent and a wet reagent are mixed. This wouldadjust the speed of the gas-generating chemical reaction, and thereforethe speed at which the force that pushes the piston is generated. Thiscould be accomplished, for example, by adjusting the size of the openingbetween the reagent chamber and the reaction chamber. For example, anadjustable aperture could be placed beneath the plunger. The aperturewould have a minimum size (to accommodate the spring), but couldotherwise be adjusted. Another way of adjusting the speed of theinjection would be to control the size of the reaction chamber. Thiswould adjust the pressure generated by the chemical reaction (becausepressure is force per area). For example, the sidewall of the reactionchamber could move inwards or outwards as desired to change the volumeof the reaction chamber. Alternately, the interior radial surface 1336could include an adjustable aperture to change the size of the orifice1331 and the rate at which gas can enter the bottom end 1334 of thereaction chamber and push on the piston 1360. Both of these methodscould be controlled by a dial on the syringe, which could mechanicallyadjust the speed of injection as desired by the user. This would allow“on-the-fly” adjustment of the speed of injection. Like other featuresdescribed herein, this feature of user-controlled adjustable speed is ageneral feature that can be applied in any of the devices describedherein.

It is also contemplated that a gas-permeable liquid-solid impermeablefilter may be present that separates the piston from the lower chamberin the injection devices described herein. In this regard, the drypowder has been found in some situations to stick to the sides of thechamber. When the piston moves, remaining solvent falls below the levelof the powder, such that further chemical reaction does not occur. It isbelieved that the filter should keep any dry solid reagent and liquidwithin the lower chamber to improve mixing.

Suitable materials for the injection devices of the present disclosureare known in the art, as are methods for making the injection devices.

The gas-generating chemical reaction used to generate force “on demand”,as opposed to springs, which only store energy when compressed. Mostautoinjectors hold a spring in a compressed position during “on theshelf” storage, causing parts to fatigue and to form over time. Anotheralternative to compressing the spring in manufacturing is to provide acocking mechanism that compresses the spring prior to use. This addsanother step to the process for using the spring-driven device. Inaddition, physically disabled users may have difficulty performing thecocking step. For example, many users of protein drugs are arthritic, orhave other conditions that limit their physical abilities. The forceneeded to activate the gas-generating chemical reaction can be far lessthan that required to activate a spring-driven device or to cock thespring in a spring-driven device. In addition, springs have a linearenergy profile. The force provided by the gas-generating chemicalreaction can be non-linear and non-logarithmic. The speed of thechemical reaction can be controlled by (i) adjusting the particle sizeof the dry reagent; (ii) changing the particle shape of the dry reagent;(iii) adjusting the packing of the dry reagent; (iv) using mixing assistdevices; and/or (v) altering the shape of the reaction chamber where thereagents are mixed.

It should be noted that silicone oil is often added to the barrel of thesyringe to reduce the release force (due to static friction) required tomove the piston within the barrel. Protein drugs and other drugs can benegatively impacted by contact with silicone oil. Siliconization hasalso been associated with protein aggregation. The forces generated bythe chemical reaction obviate the need for application of silicone oilto the barrel of the syringe. In other words, no silicone oil is presentwithin the barrel of the syringe.

When a solvent is used to form a medium for a chemical reaction betweenchemical reagents, any suitable solvent may be selected. Exemplarysolvents include aqueous solvents such as water or saline; alcohols suchas ethanol or isopropanol; ketones such as methyl ethyl ketone oracetone; carboxylic acids such as acetic acid; or mixtures of thesesolvents. A surfactant may be added to the solvent to reduce the surfacetension. This may aid in improving mixing and the subsequent chemicalreaction.

The following examples are for purposes of further illustrating thepresent disclosure. The examples are merely illustrative and are notintended to limit processes or devices made in accordance with thedisclosure to the materials, conditions, or process parameters set forththerein.

EXAMPLES

A test rig 1000 for carrying out experiments is shown in FIG. 10. Astandard prefilled syringe 1040 was filled with 1 ml fluid. Starting atthe left of the figure, a prefilled syringe 1040 was fitted with a 19 mmlong and 27 gauge thin walled needle 1006 and stopped with a standardstopper 1066. This syringe 1040 acted as the fluid chamber. Connected tothe prefilled syringe was a reaction chamber syringe 1030. A piston rod1064 and a push surface 1062 were used to apply force from the chemicalreaction to the stopper 1066. A one-way pressure valve 1050 was used toallow injection of solvent from a second “injector” syringe 1020 thatacted as the reagent chamber. The set-up was clamped into the testfixture 1010. A graduated pipette (not shown) was used to measure thevolume delivered versus time.

Example 1

Two fluids were tested, water (1 cP) and silicone oil (73 cP). Waterserved as the low-viscosity fluid, silicone oil served as thehigh-viscosity fluid. One of these two fluids was added to the prefilledsyringe 1040 depending on the experiment. To the reaction chambersyringe 1030 was added 400 mg NaHCO₃ and 300 mg citric acid, as drypowders. The injector syringe 1020 was filled with either 0.1 ml, 0.25ml, or 0.5 ml water. The water was injected into the reaction syringe1030 (the volume of the reaction syringe was adjusted based on thevolume to be delivered by the injector syringe). The delivered volumeversus time and total delivery time were measured. The pressure wascalculated using the Hagen-Poiseuille equation and assumed there was 0.6lb frictional force between the stopper 1066 and the prefilled syringe1040. Alternatively, the force on the prefilled syringe 1040 wasdetermined by placing a load cell at the exit. The results are shown inTable 1 and were based on a minimum of at least three runs.

The chemical reaction syringe provided delivery of 1 mL water in 5seconds or less. The delivery time for the higher viscosity fluiddepends on the volume of water injected. Surprisingly, the delivery timeis faster when the volume of water is greater. This is surprisingbecause water, which doesn't participate in the reaction, serves todilute the reagents. Reaction kinetics, and production of CO₂, decreaseas the concentration of reagents decreases. The results indicate theimportance of the dissolution kinetics. The dissolution is faster forhigher volume of water. Using 0.5 mL of water, high viscosity fluid canbe delivered in 9 seconds. Thus, in some preferred embodiments, theinvention provides for delivery of substantially all of a solution (ofat least 0.5 ml, or 0.5 to 3.0 mil or 1 ml) having a viscosity of atleast 20 cP, preferably at least 40 cP and in some embodiments belowabout 70 cP within 20 seconds or within 15 seconds or within 10 secondswith a chemical engine comprising a starting volume (prior to expansion)of less than 1.0 ml, in some embodiments within the range of 0.3 to 1.0ml; in some embodiments, the ratio of the volume of water in thechemical engine to volume of medicament is less than 2:1, preferablyless than 1:1, less than 0.5:1 and in some embodiments in the range of1:1 to 0.3:1. Throughout this description, viscosity is measured (ordefined) as the viscosity at 25° C. and under the delivery conditions.

TABLE 1 Injection Syringe Time to Deliver 1 mL Time to Deliver 1 mL (mLwater) water silicone oil 0.1 5  24 ± 9.0 0.25 4.5 ± 0.5 16.38 ± 4.62 0.5   4 ± 1.0 9.5 ± 0.5 1.0 2.21 ± 0.89 8.89 ± 0.19 2.0 1.25 ± 0.77  6.5± 0.79 3.0 1.35 ± 0.28 5.58 ± 0.12 4.0 1.10 ± 0.14 6.54 ± 0.05

FIG. 22 is a graph showing the pressure versus time profile for deliveryof silicone oil when 0.1 ml (triangle), 0.25 ml (square), and 0.5 ml(diamond) of water was injected into the reaction chamber. This graphshows that a nearly constant or diminishing pressure versus time profilecould be obtained after a ramp-up period, although the impact of volumeexpansion dominated at longer times. These pressure versus time profileswere not exponential. A constant pressure versus time profile may allowfor slower, even delivery of a high-viscosity drug, as opposed to asudden exponential burst near the end of a delivery cycle.

Example 2

Sodium chloride (NaCl) was used to enhance the release of gaseous CO₂from the reaction solution in the reaction chamber, accelerating theincrease in pressure. In control experiments, citric acid and NaHCO₃were placed in the reaction syringe. A solution of 1.15 M NaHCO₃ inwater was injected into the reaction syringe from the injector syringe.The empty volume in the reaction syringe was kept constant through allexperiments. In experiments demonstrating the concept, NaCl was added tothe reaction syringe. The chemical reaction was used to deliver 1 ml ofwater or silicone oil from the prefilled syringe. The delivered volumeversus time and total delivery time were measured. The pressure wascalculated using the Hagen-Poiseuille equation and assumed there was a0.6 lb frictional force between the prefilled plunger and the syringe.Note that bicarbonate was present in the water injected into thereaction syringe, so that gas could be generated even if solidbicarbonate was not present in the reaction syringe itself. The resultsare shown in Table 2.

TABLE 2 Reagents in Injection Time to Time to Reaction Syringe SyringeDeliver Deliver (mg) (mL) 1 mL 1 mL Solid Citric 1.15M aq. watersilicone No NaHCO₃ Acid NaCl NaHCO₃ (sec) oil (sec) 1 350 304 0 0.5 1.38± 0.05 8.3 ± 0.8 2 350 304 121 0.5 1.69 ± 0.03 7 ± 1 3 50 76 0 0.5 4 134 50 76 121 0.5 4.9 ± 0.6 11 5 0 38 0 0.5 24 ± 1  41 ± 7  6 0 38 121 0.59 ± 2 20.5 ± 0.5 Salt served to significantly enhance the delivery rate, particularly forsystems that used smaller amounts of reagent. A high viscosity fluidcould be delivered in 6 to 8 seconds using the chemical reaction. Thisis significantly faster than what can be achieved with standardauto-injectors that employ mechanical springs.

FIG. 23 shows the delivered volume versus time profile for experimentNos. 5 and 6 of Table 2. A high viscosity fluid was delivered in 20seconds using a system having a footprint of less than 1 cm3. Thedelivery rate (i.e. slope) was also relatively constant. The smallfootprint enables a variety of useful devices.

Example 3

Several different reagents were tested to show the influence of powdermorphology and structure on the pressure profile. Morphology, in thiscase, refers to the surface area, shape, and packing of molecules in thepowder. The same bicarbonate (sodium bicarbonate) was tested. Threedifferent morphologies were created—one as-received, one freeze-dried,which was produced by freeze drying a 1.15 M solution, and one where thebicarbonate was packed into a tablet “Layering” of the reagents in thereaction chamber was also examined; where layering refers topreferential placement of reagents within the reaction cylinder. Inanother example, Alka Selzter, which contains citric acid and sodiumbicarbonate in a matrix, was used.

The following reagents were used: as-received baking soda (NaHCO₃),citric acid, freeze-dried baking soda, Alka-Seltzer, or as-receivedpotassium bicarbonate (KHCO₃). The as-received baking soda was alsotested as a powder, or in a tablet form. The tablet form had a decreasedsurface area.

The freeze-dried baking soda was formulated by preparing 125 ml ofsaturated baking soda aqueous solution (1.1 SM). The solution was pouredinto a 250 ml crystallization dish and covered with a Kimwipe. Thesolution was placed in a freeze dryer and was ramped down to −40° C. andheld for two hours. The temperature remained at −40° C., and a vacuumwas applied at 150 millitorrs (mTorr) for 48 hours. Alka-Seltzer tablets(Effervescent Antacid & Pain Relief by Kroger) were broken up using amortar and pestle into a coarse powder.

Baking soda tablets were prepared by pouring 400 mg of as-receivedbaking soda powder in a die to produce a tablet with a 1 cm diameter.The die was swirled around to move the powder to give an even depthacross the 1 cm. The die was placed in a press and held at 13 tonspressure for 1 minute. Tablets weighing 40 mg and 100 mg were brokenfrom the 400 mg tablet.

The Apparatus and Plan

The previously described test rig was used. The 3 ml injection syringewas filled with 0.5 ml of de-ionized water. The 10 ml reaction syringewas connected to the injection syringe by luer locks and a valve, andthen clamped down tightly in the apparatus. A load cell was attached tothe plunger rod so the reaction syringe plunger presses on it during thetest. This recorded the applied force from the reaction while displacingthe fluid in the prefilled syringe.

The fluid from the prefilled syringe was displaced into a graduatedsyringe which was video recorded. This observed the change in volume ofthe fluid over time. The fluids were water (1 cP) or silicone oil (73cP), which were displaced through a 27 gauge thin-walled prefilledsyringe and had a volume of 1 milliliter (ml).

Two measurements were acquired while during each test: the force on theprefilled syringe using a load cell and the change in volume of theprefilled syringe by measuring the dispensed volume with time. Theaverage volume vs. time curve was plotted to show how each reactionchanged the volume in the prefilled syringe. The pressure vs. time curveusing the Hagen-Poiseuille equation was provided by calculating the flowrate from the volume vs. time curve. To account for the friction in theprefilled syringe, 94,219 Pa was added (which is equivalent to 0.6 lb).This calculated the pressure inside the prefilled syringe (3 mm radius)so the hydraulic equation was used (P₁A₁=P₂A₂) to calculate the pressureinside the reaction syringe (6.75 mm diameter). This was used to checkthe measurement made by the load cell.

Another pressure vs. time curve was produced by using the force in theload cell measurement and dividing by the area of the reaction plunger.We found this to provide more reproducible data than the calculation byHagen-Poiseuille.

To determine how the pressure changed with volume, pressure vs. volumecurves were produced. The pressures used were those calculated by theload cell measurements. The reaction volume was calculated using thechange of volume in the prefilled syringe. The volume of the reactionsyringe (VR) could be determined from the dispensed volume in theprefilled syringe (Vp) at time t.

Finally, the reaction rate while dispensing the fluid was found by usingthe ideal gas law where PR is the pressure calculated from the loadcell, VR is the volume of the reaction syringe, R is the universal gasconstant (8.314 Jmol⁻¹K⁻¹), and T is the temperature, 298K.

The Tests

The baseline formulation was 400 mg of baking soda, 304 mg of citricacid, and 0.5 ml of de-ionized water as described in Example 1. Thisformulation produces 4.76×10−3 moles of CO₂ assuming 100% yield. Theingredients of all tests were formulated to produce the same 4.76×10-3moles of CO₂ assuming 100% yield. Four sets of tests were performed.

The first set used as-received baking soda (BSAR) and freeze-driedbaking soda (BSFD). Their relative amounts were varied in increments of25%. 304 mg citric acid was also included in each formulation. Table 3Aprovides the target masses of the baking soda for these tests.

TABLE 3A Target Mass [mg] Test BSAR BSFD 100% BSAR 400 0  75% BSAR 300100  50% BSAR 200 200  25% BSAR 100 300 100% BSFD 0 400

The second set used as-received baking soda and Alka-Seltzer. The amountof as-received baking soda was varied in increments of 25%. Thestoichiometric amount of citric acid was added. Alka-Seltzer is onlyapproximately 90% baking soda/citric acid. Therefore, the total mass ofAlka-Seltzer added was adjusted to obtain the required mass of bakingsoda/citric acid. Table 3B provides the target masses of each ingredientfor these tests.

TABLE 3B Target Weight [mg] Test Baking Soda Citric Acid Alka-Seltzer100% BSCA 400 304 0  75% BSCA 300 228 196  50% BSCA 200 152 392  25%BSCA 100 76 586 100% Alka-Seltzer 0 0 777

The third set used as-received baking soda and as-received potassiumbicarbonate. The mass of citric acid was maintained at 304 mg throughoutthe tests. Due to the heavy molar mass of potassium bicarbonate (100.1g/mol as opposed to baking soda's 84.0 g/mol), more mass is required togenerate the same moles of CO₂. Table 3C provides the target masses (inmg) of each ingredient for these tests.

TABLE 3C Test Baking Soda Potassium Bicarbonate 100% BS 400 0  50% BS200 239 100% KHCO3 0 477

The fourth set used the baking soda tablets. The stoichiometric amountof citric acid was used. No other reagents were added. Table 3D providesthe target masses (in mg) of each ingredient for these tests.

TABLE 3D Test Baking Soda Tablet Citric Acid 400BS-304CA 400 304100BS-76CA 100 76 40BS-30CA 40 30

Results of the Tests

First Set: as-received baking soda (BSAR) and freeze-dried baking soda(BSFD).

The freeze-dried baking soda powder appeared coarse relative to theas-received baking soda powder. It was also less dense; 400 mg of thefreeze-dried powder occupied 2 ml in the reaction syringe, whereas theas-received powder only occupied 0.5 ml. Due to the volume of material,the smaller volume of water (0.5 ml) was insufficient to fully contactall of the freeze-dried baking soda. Thus, in “100%”, “75%”, and “50”experiments, the bicarbonate was not fully wetted, dissolved or reacted.Therefore, a fifth formulation was run where the freeze-dried sample wasinserted first. It was followed by the citric acid and then theas-received powder. It was labeled as “50% BSAR Second”. Thisformulation permitted the injected water to come into contact first withthe freeze-dried powder, then contact and dissolve the citric acid andthe as-received powder. The time needed to displace 1 ml of the siliconeoil is listed in Table 3E.

TABLE 3E Formulation Time (sec) 100% BSAR 10  75% BSAR 13  50% BSAR 11 50% BSAR Second 22 100% BSFD 14

The volume vs. time graph is seen in FIG. 24. It appeared that the 100%freeze-dried powder was initially faster than the 100% as-receivedpowder but slowed over time. The as-received powder took 10 seconds todisplace 1 ml, and the freeze-dried powder took 14 seconds. As expected,the trials with mixed amounts were found to have times between the twoextremes.

The pressure vs. time graph is given in FIG. 25. The formulations with100% BSAR showed a maximum pressures nearly 100,000 Pa higher than thosewith 100% BSFD. In comparison, using “75% BSAR” gave a faster pressureincrease and slower decay. For ease of comparison, the pressures werenormalized and plotted in FIG. 26 and FIG. 27 (two different timeperiods).

The 100% BSAR had an initial slow reaction rate compared to the 75% BSARand 50% BSAR formulations. This suggests the freeze-dried baking soda(BSFD) dissolves and reacts faster, and this is seen in FIG. 22.However, FIG. 21 shows that as the freeze-dried baking soda contentincreases, a lower maximum reaction pressure is obtained. Due to the lowdensity of the freeze dried powder, 200 mg of the freeze-dried bakingsoda occupies 1 ml of space, so the 0.5 ml of de-ionized water cannotcontact all of the material before the generated gas moves the plunger,leaving the dry powder behind stuck on the side of the chamber; not allof the freeze-dried baking soda was reacted and less CO2 was produced.It was estimated for the 100% BSFD trial that only a quarter of thereagent dissolved. This phenomenon may be reduced by modifying thechamber devices, for example where the gas-generating chemical reactionoccurs in a rigid chamber, with the generated CO2 diffusing through afilter to push the plunger.

In the 50% BSAR Second trial, when the freeze-dried baking soda wasadded first followed by the citric acid and as-received baking soda,much of the powder remained solid, resulting in a lower pressure. Thelow initial reaction was most likely caused by the 0.5 ml of waterdiffusing through the 1 ml of freeze-dried baking soda powder beforereaching and dissolving the citric acid. This test was the closest ofthe trials in this set to providing a constant pressure profile.

The maximum pressure obtained was at approximately 0.8 ml CO₂ volume forthe 50% BSAR and 75% BSAR formulations. These formulations also had thefastest rate in the pressure vs. time graphs (see FIG. 26). Theremaining formulations had maximum pressures at approximately 1.2 mlCO₂.

Interestingly, when looking at FIG. 23 and FIG. 24, the “50% BSARSecond” showed a distinct pressure vs. time profile (Pa s in FIG. 23),but had approximately the same pressure vs. volume profile as the 100%BSFD in FIG. 24. Referring back to Table 3E, it took approximately 8seconds longer for the “50% BSAR Second” to displace the 1 ml ofsilicone oil, so its pressure curve is “drawn out” relative to the 100%BSFD, and it had a different flow rate. The results indicate that ispossible to reduce the pressure drop that accompanies piston motion (andvolume expansion of the reaction chamber) by including bicarbonates withtwo different dissolution rates, where the different dissolution ratesare provided by their morphology and/or position in the reactionchamber.

Table 3F shows the reaction rates for production of CO2 versus timefitted to y=ax²+bx.

TABLE 3F Formulation First Term (a) Second Term (b) 100% BSAR 0 5 × 10⁻⁵ 75% BSAR 0 4 × 10⁻⁵  50% BSAR 0 4 × 10⁻⁵  50% BSAR Second −5 × 10⁻⁷ 2 ×10⁻⁵ 100% BSFD −1 × 10⁻⁶ 2 × 10⁻⁵The 100% BSAR, 75% BSAR, and 50% BSAR curves have approximately the samelinear reaction rate. The “50% BSAR Second” forms a second orderpolynomial. The “100% BSFD” appears to be parametric; it has the samelinear rate as 100% BSAR and the other two, and then the slope suddenlydecreases after 5 seconds and converges with “50% BSAR Second.”

Second Set: as-received baking soda and Alka-Seltzer.

The volume vs. time graph is seen in FIG. 28 for silicone oil, and inFIG. 29 for water as the injected fluids respectively. The time neededto displace 1 ml of each fluid is listed in Table 3G. The error in timemeasurement is estimated to be half a second.

TABLE 3G Time (sec) Formulation Silicone Water 100% BSCA   11 ± 0.95 3 75% BSCA 14.78 ± 1.35 3.2  50% BSCA  12.5 ± 2.12 2.27 ± 0.47  25% BSCA10.11 ± 1.02 3 100% Alka-Seltzer 11 2

The times for displacement of water are difficult to compare becausethey are all within one second of each other. The volume profiles for100% BSCA, 25% BSCA, and 100% Alka-Seltzer had the fastest times todisplace 1 ml of silicone oil. The 100% BSCA appeared to start slowlyand then speed up. The 50% BSCA and 75% BSCA were found to have theslowest times. They appeared to slow down as the displacement proceeded.

The pressure vs. time graph is given in FIG. 30 for silicone oil, and inFIG. 31 for water as the injected fluids respectively. The 100% BSCA hadthe slowest initial pressure rise. This was expected, since Alka-Seltzeris formulated to allow fast diffusion of water into the tablet. The 75%BSCA and 50% BSCA had the second and third greatest maximum pressure,respectively, for silicone oil. However, these two formulations took thelongest to displace 1 ml of silicone oil. Their pressures also had theslowest decay. This is most likely due to increased friction in thesyringe.

The curves in FIG. 31 for water are within a reasonable error of eachother. However, they were greater than the estimated pressures byHagen-Poiseuille, which calculated the maximum pressure to be 51,000 Paby the 100% Alka-Seltzer formulation. High friction was not observedduring testing.

Normalized pressure vs. time graphs are provided for silicone oil inFIG. 32. The pressure decay rate for silicone oil is provided in Table3H.

TABLE 3H Formulation Decay Rate (Pa/s) 100% BSCA 6,854  75% BSCA 4,373 50% BSCA 3,963  25% BSCA 9,380 100% Alka-Seltzer 10,695

For silicone oil, the 100% BSCA and the 75% BSCA had the same normalizedpressure increase, but different decays. As explained above, the 75%BSCA may have undergone more friction causing the change in volume toslow and hold pressure longer. The same was true for the 50% BSCA, whichhad the same decay as 75% BSCA. Surprisingly, the pressure increase for50% BSCA fit just between 100% BSCA and 100% Alka-Seltzer. This mayindicate that friction does not affect the pressure increase. The 100%Alka-Seltzer and 25% BSCA had the same pressure profiles with thefastest pressure increase and fastest decay. The 100% BSCA also appearedto have the same decay as these two formulations.

For water, it was found that higher ratios of Alka-Seltzer to BSCAresulted in relatively less pressure decay. The 100% Alka Seltzer had afast pressure increase but quickly decayed along with 100% BSCA″ and 75%BSCA. However, 25% BSCA and 50% BSCA had fast pressure increase and lesspressure decay than the other formulations.

For silicone oil, the 100% Alka-Seltzer, 50% BSCA, and 75% BSCA allpeaked at approximately 1.2 ml of CO₂ volume. The 25% BSCA peaked atapproximately 0.8 ml. The 100% BSCA did not reach maximum pressure untilapproximately 1.6 ml. This was slightly different than the “100% BSAR”in the first set of tests, which used the exact same formulation butreached its maximum pressure at a CO₂ volume of 1.2 ml.

Table 3I shows the reaction rates for CO2 production during injection ofsilicone oil fitted to y=ax²+bx.

TABLE 3I Formulations First Term (a) Second Term (b) 100% BSCA 0 4 ×10⁻⁵  75% BSCA 0 3 × 10⁻⁵  50% BSCA 0 3 × 10⁻⁵  25% BSCA 0 4 × 10⁻⁵ 100%Alka-Seltzer −2 × 10⁻⁶ 6 × 10⁻⁵

All formulations except 100% Alka-Seltzer formed linear reaction ratesfor silicone oil. The high friction in the prefilled syringe used totest 75% BSCA and 50% BSCA caused a high pressure, which may havereduced the reaction rate to 3×10⁻⁵ mol/s. The 100% BSCA and 25% BSCAhad the same reaction rate at 4×10⁻⁵ mol/sec. 100% Alka-Seltzer resultedin a second order polynomial. It initially had the same reaction rate asthe other formulations, but the slope decreased in the last few seconds.When the reaction was finished, the solution was much thicker than theother formulations.

The 100% BSCA was slightly slower than the previous experiment withfreeze-dried baking soda, 100% BSAR (see Table 3F), by 1×10⁻⁵ mol/sec.This may have caused the slower time to displace the silicone andpossibly the maximum pressure at a greater CO₂ volume at 1.6 ml.

Third Set: as-received baking soda and as-received potassiumbicarbonate.

The volume vs. time graph is seen in FIG. 34, for silicone oil. The timeneeded to displace 1 ml of each fluid is listed in Table 3J.

TABLE 3J Formulation Time (sec) 100% BS 8.00  50% BS 8.00 100% KHC036.33

The 100% KHCO₃ was the fastest to displace the 1 ml of silicone at 6.33seconds. The 100% BS and 50% BS displaced the same volume at a time of8.00 seconds.

The pressure vs. time graph is given in FIG. 35. The pressure decay ratefor silicone oil is provided in Table 3K.

TABLE 3K Formulation Pressure Decay (Pa/sec) 100% BS 6,017  50% BS 7,657100% KHC03 11,004The 100% BS formulation only reached a maximum pressure of approximately250,000 Pa, while the other two formulations had a maximum pressure ofapproximately 300,000 Pa. The 100% KHCO₃ and 50% BS formulations (eachcontaining potassium bicarbonate) continued increasing in pressure for afew seconds after the 100% BS reached its maximum. The 50% BSformulation initially had less pressure as expected but was able tomaintain a higher pressure after 6 seconds compared to the 100% KHCO₃.The results showed that using a mixture of sodium and potassiumbicarbonate can produce higher pressures and slow decays.

The 100% BS had a peak pressure somewhere between 0.6 and 1.8 ml of CO₂.The curves for 50% BS and 100% KHCO₃ were different from the otherpressure vs. volume graphs seen previously. Instead of peaking atapproximately 1.2 ml of CO₂ volume and decaying, they continuedincreasing in pressure at greater CO₂ volumes. The 50% BS and 100% KHC03formulations peaked at approximately 2.0 and 3.2 ml of CO₂ volume,respectively.

Table 3L shows the reaction rates fitted to y=bx.

TABLE 3L Formulation Rate (mol/sec) 100% BS 5 × 10⁻⁵  50% BS 9 × 10⁻⁵100% KHC03 1 × 10⁻⁴They appeared to be linear reaction rates with 100% BS at 5×10⁻⁵ mol/sec(the same rate from the experiments above). 100% potassium bicarbonatehas twice the rate as baking soda.

Fourth Set: baking soda tablets.

The volume vs. time graph is seen in FIG. 43 for silicone oil. The timeneeded to displace 1 ml of each fluid is listed in Table 3M.

TABLE 3M Time (sec) Baking Soda Tablet (mg) Silicone Water 400 42 25.67100 104 78 40 247 296

For both silicone oil and water, using 400 mg and 100 mg baking sodatablets and the stoichiometric citric acid resulted in nearly straightlines. Packing the baking soda into dense tablets significantlydecreased reaction rates, and thus increased injection times, relativeto other baking soda experiments. Table 3N shows the reaction ratesfitted to y=ax²+bx.

TABLE 3N Silicone Oil Water Second Second Formulations First Term (a)Term (b) First Term (a) Term (b) 400 BS 0 4 × 10⁻⁶ 3 × 10⁻⁸ 2 × 10⁻⁷ 100BS 0 7 × 10⁻⁷ N/A N/A  40 BS −4 × 10⁻¹⁰ 2 × 10⁻⁷ N/A N/AFor silicone oil, the 400 mg BS tablet showed the linear reaction rateas 4×10⁻⁶ mol/sec. The 100 mg baking soda tablet was linear for almost87 seconds until it suddenly stopped producing gaseous CO₂. The reactionrate for the 40 mg tablet was a second order polynomial and very slow.It reached a total of 2×10⁻⁵ moles CO₂ and stayed steady with somefluctuation possibly caused by the CO₂ moving in and out of solution.Due to the small reaction rate in water, only the 400 mg tablet wasused.

The results of Example 3 showed the ability to create different pressureversus time profiles when the dissolution kinetics are modified.

Example 4

The test rig was used to test silicone oil and a 27 gauge thin-wallneedle. The stoichiometric reaction and results are shown in Table 4below.

TABLE 4 Reagents Injection Time to in Reaction Syringe (mL) Deliver 1 mLSyringe (mg) Saturated silicone Citric Acid NaCl KHCO₃ oil (sec) 140 2000.5 8

Example 5

The prototype test device illustrated in FIG. 19 was tested usingsilicone oil. A pre-filled syringe acted as the fluid chamber from whichfluid was ejected. Next, a connector was used to join the pre-filledsyringe with the reaction chamber. The reaction chamber included amixing. A piece of filter paper was placed inside the reaction chamberto cover the orifice to the arm. A spring was then placed inside themixing chamber. Next, a plunger was used to separate the dry reagent inthe reaction chamber from the wet liquid. The next piece was the pushbutton, which included an interior volume for the liquid reagent. Thepush button included a hole (not visible) that was used to fill thevolume with liquid reagent. A screw was used to fill the hole in thepush button. A cap was fitted over the push button to provide structuralsupport, and also surrounds a portion of the reaction chamber. Finally,a thumb press was placed on top of the cap for ease of pressing. Boththe reagent chamber and the reaction chamber were completely filled withliquid solution and dry powder, respectively.

The syringe was tested in both the vertical position (reagent chamberabove reaction chamber) and the horizontal position (the two chambersside-by-side). The reagents and results are shown in Table 5 below.

TABLE 5 Reagents Reagent Time to in Reaction Chamber (mL) Deliver 1 mLChamber (mg) Saturated silicone Orientation Citric Acid NaCl KHCO₃ oil(sec) Vertical 250 200 0.75 8.5 Horizontal 250 200 0.75 17Assuming adequate mixing, the potassium bicarbonate is the limitingreactant, with citric acid at an excess of 89 mg. This assumption wasfound to be incorrect because liquid was found in the top chamber andpowder was found in the bottom chamber when disassembled. When thesyringe was laid in a horizontal position, and the chambers werecompletely filled, the silicone oil was displaced in 17 seconds. Thisillustrates that the device can work in any orientation. This is helpfulfor permitting patients to inject into their abdomen, thigh, or arm,which are the most common locations for self-injection.

Example 6 Mixed Bicarbonates

In the test apparatus of Example 1 was modified to contain a mixture of50:50 molar mixture of sodium and potassium bicarbonate. Delivery of thesilicone oil was accommodated in a faster time (just under 8 sec) andthe pressure versus time was flat. The flow increased and then reached aplateau in just under 2 seconds. The use of mixed bicarbonates allowsfor a system that has different reaction kinetics to control thepressure profile.

Example 7 Use of a Nucleating Agent to Enhance Release of CO2

Sodium Chloride (NaCl) was used to enhance the release of gaseous CO2from the reaction solution into the reaction chamber, accelerating theincrease in pressure. In control experiments, citric acid and NaHCO3 wasplaced in the reaction syringe. A solution of 1.15 M NaHCO3 in water wasinjected into the reaction syringe. The empty volume in the reactionsyringe was minimized through all experiments and was dictated by thedensity of the powder. In experiments demonstrating the concept of theinvention, NaCl was added to the reaction syringe. The chemical reactionwas used to deliver 1 mL of water or silicone oil. The delivered volumeversus time and total delivery time were measured. The pressure wascalculated using Hagen-Poisuielle equation, considering the area of theplungers, and assumes there is a 0.61b frictional force between theprefilled syringe plunger and the syringe.

Salt serves to significantly enhance the delivery rate, particularly forsystems that use smaller amounts of reagent. A high viscosity fluid canbe delivered, for example, in 6 to 8 seconds using the chemicalreaction. This is significantly faster than what can be achieved withstandard auto-injectors that employ mechanical springs. The deliveredvolume versus time is shown for the smallest chemical-reaction. A highviscosity fluid was delivered in 20 seconds using a system having afootprint of less than 0.5 cm³. The small footprint enables a variety ofuseful devices.

Reagents in Injection Time to Reaction Syringe Syringe Time to Deliver(mg) (mL) Deliver 1 mL Solid Citric 1.15M aq. 1 mL silicone No NaHCO3Acid NaCl NaHCO3 water oil 1 350 304 0 0.5 1.38 ± 0.05  8.3 ± 0.8 2 350304 121 0.5 1.69 ± 0.03  7 ± 1 3 50 76 0 0.5 4 13 4 50 76 121 0.5 4.9 ±0.6 11 5 0 38 0 0.5 24 ± 1  41 ± 7 6 0 38 121 0.5 9 ± 2 20.5 ± 0.5

Example 8 Use of Reagents with Two Dissolution Rates to Modify PressureVersus Time Profile

Reagents with two different dissolution rates were created by combiningNaHCO3 with two different morphologies (preferably, different surfacesareas). For example mixtures can be prepared using bicarbonates obtainedfrom different sources, or treating a portion of the bicarbonate priorto combining with an untreated portion. For example, a portion can befreeze-dried to increase surface area. High surface area NaHCO₃ wasproduced by freeze drying a 1.15 M solution. Reagents with two differentdissolution rates were also created by combining as-received sodiumcitrate/NaHCO₃ and formulated sodium citrate/NaHCO3 (Alka Seltzer). Theresults show the ability to create different pressure versus timeprofiles when the dissolution kinetics are modified.

Example 9 Minimization of Pressure Decrease with Expansion of Piston

Chemical engines were created to deliver fluids with viscosity from 1 to75 cP and volumes of 1 to 3 mL in less than 12 seconds through a 27gauge needle. In the experiments of this example, the dry chemical werepremixed in a jar and then added to the reaction syringe (B). Thereaction syringe consisted of either a 10 mL or 20 mL syringe. Theplunger was fully depressed on the powder so that no additional emptyvolume was present. A solution was added to the reaction syringe; as CO₂was generated, the plunger rod pressed against the plunger of the PFSand delivered fluid. Six engine formulations were considered, as shownin the Table.

Solution Added to Amount of Time to Time to Reaction Dry Chemicals inFluid Deliver 20 cP Deliver 50 cP Formulation Chamber Reaction ChamberDelivered Fluid (s) Fluid (s) 1 0.5 mL 107 mg citric acid 1 mL 4 7saturated 200 mg NaCl KHCO3 2 0.75 mL 160 mg citric acid 1 mL 2.5 5saturated 100 mg NaCl KHCO3 3 1.0 mL 800 mg KHCO3 (s) 3 mL n/a 9.5saturated 610 mg citric acid KHCO3 4 1.0 mL water 1130 mg KHCO3 3 mL n/a11 (s) 610 mg citric acid 5 2.5 mL water 2530 mg KHCO3 3 mL n/a 6.5 (s)1500 mg citric acidThe force versus time profiles are shown for the different chemicalengines in FIGS. 40-42. Formulations 1 and 2 were used to deliver 1 mLof fluid through a 27 gauge thin wall needle; i.e. a standard PFS.Fluids with viscosity of 25 and 50 cP were examined. Faster delivery isachieved when the amount of reagent is increased. The use of potassiumbicarbonate allows for substantially less reagent to be employed thanwhen sodium bicarbonate is used.

Formulations 3, 4, and 5 were used to deliver 3 mL of 50 cP fluidthrough a 27 gauge thin wall needle. The target flow rates were higherthan those targeted for Formulations 1 and 2. In this case, simplyscaling up the reaction to larger amounts (Formulation 3) results insubstantial initial overshoot in the force, due to rapid reaction. Theovershoot was reduced by employing 100% solid reagents (mixture ofcitric acid and potassium bicarbonate in the reaction chamber) and waterduring the injection. This method provided a steady-state of CO₂ as thewater dissolved the potassium bicarbonate and made bicarbonate ionsavailable. Formulation 5 exhibited a flat delivery profile and delivered3 mL of 50 cP fluid in 6.5 s.

Example 10 Addition of Convection Agents

The addition of a small amount (for example, <10 mg for a 1 mL engine)of slowly dissolving or insoluble particles was found to be effective insubstantially increasing the rate of gaseous CO₂ generation and themaximum gaseous CO₂ generated, substantially increasing the powerdensity of the engine. Surprisingly, we found the surface energy andsurface topology of the particles to have only a minor effect, as avariety of slowly dissolving or insoluble particles work, includingdiatomaceous earth, Expancel™ (polyacrylonitrile hollow microspheres),calcium oxalate, and crystalline oxalic acid. In this case, slowlydissolving means that the particle is slow relative the reagents in theengine. The presence of these particles can be determinedexperimentally, by dissolving the solid reagents and looking for thepresence of particles or determining the identity of the materialspresent and comparing their solubility products. The density can beeither lower than or higher than water.

We believe that these agents act alone, or in concert with gaseous CO₂leaving the fluid, to set-up mixing fields, similar to those that mightbe found in fluidized beds. The mixing fields increase the collisionsbetween reagents and between the convection agents and reagents. Theseincreased collisions serve to release kinetically trapped CO₂ that mayexist at surfaces and crevices, such as on the container or onbicarbonate surfaces.

Our results indicate that these reagents are not serving primarily asnucleating agents, though that could be a minor factor. The reagents areeffective in conditions where the reaction chamber is fixed to constantvolume, or allowed to expand. Under constant volume circumstances, thepressure does not decrease, and the solution is never supersaturated,as, for example, might be seen in a pressurized carbonated beverage thatis opened to atmosphere. Furthermore, the addition of nucleatingsurfaces, for example porous aluminum, is ineffective. The reagents mustbe present as particles in the engine.

Experiments were carried out in one of two set-ups.Constant Volume: The constant volume setup was used to compare differentchemical reaction times. Reagents were placed in a 2 ml reactionchamber; liquid reactants were added to the chamber by using a syringeand injecting into the reaction chamber at the desired time of injectionand the valve was closed. Pressure was measured by a pressure transducerand temperature by thermocouple. As the reaction occurred, pressure fromthe chamber was channeled into the air cylinder through a small tube.The air cylinder was used as an equivalent to a piston/plunger in a realinjection system. For the constant volume setup, the air cylinder wasinitially moved 1.5 inches to the end of the injection position for a 2ml syringe and kept at that location throughout the test. This gave atotal volume of the reaction chamber and the air cylinder was 9.9 ml. Aload cell was used to measure force as a back up to pressure, but couldhave been calculated from the pressure and area of the piston in thecylinder. The advantage of using a constant volume setup to look atinitial chemical selection was that it allowed a good comparison ofpressure versus time profiles without having to take into account thedifferences in volume that a real system would have.

Test Conditions

The following chemicals were tested as received: sodium bicarbonate,potassium bicarbonate, citric acid, tartaric acid, oxalic acid, calciumoxalate, diatomaceous earth, and Expancel™. Anodized aluminum oxide wasprepared by anodization of aluminum in oxalic acid to create poroussurface structure and high surface energy.Reactants were loaded into either the reaction vessel or as a solutionto the syringe. The reaction vessel generally contained the acid, as asolid or solution, with or without any additives. The syringe containedthe bicarbonate solution. The reactants (bicarbonate and acid) weremeasured out as powders on an analytical balance in stoichiometricratios. The masses of reactants are displayed in the following Table.

TABLE Masses of reactants used for testing. Reaction 1 Reaction 2 KHCO₃(mg) 630.0 NaHCO₃ (mg) 528.6 C₆H₈O₇ (anhydrous) (mg) 403.0 C₆H₈O₇(anhydrous) (mg) 403.01 mL of water was used to dissolve the bicarbonate and supply them amedium where the reaction could evolve within the reaction chamber ofthe ChemEngine.There were 4 different types of convection agents added to the chemicalformulation, a nucleation surface was added to the reaction chamber, andexternal vibration was also added to the reaction chamber in separateexperiments.

-   -   1. Water insoluble with high density—Diatomaceous Earth (DE)    -   2. Water insoluble with low density—Polyacrylonitrile (PAN)        hollow micro-spheres    -   3. Water slightly soluble—Calcium Oxalate    -   4. Water highly soluble—Sodium Chloride and Oxalic Acid    -   5. Nucleation surface—Anodized Aluminum Oxide    -   6. Mechanical vibration        All of the convection agents (1-4) were added as dry particles        to at loading between 5 mg and 50 mg to the chemical        formulation. The nucleation surface (anodized aluminum oxide)        was added into the reaction chamber.

As shown in the FIG. 43, all of the convection agents increased the rateof pressure accumulation over the baseline formulation. In this case,the baseline formulation is the same amount of potassium bicarbonate,citric acid, and water, but no other chemicals present. Mechanicalvibration also increased the rate of pressure accumulation over thebaseline formulation. A nucleation surface had very little effect on therate of pressure accumulation. The data in FIG. 43 are provided to showthat the convection agents functioned to increase the collision ratebetween reactants, and between reactant and products, to release CO₂into the gas phase at an increased rate. The data show that addition ofthe convection agents operated by a differentiated mechanism, andincreased the reaction chamber pressure more quickly from that of anucleation agent. The data in FIG. 44 show that mechanical vibration (70Hz from a Vibra-Flight™ Controller) and convection agents have a similareffect on the rate at which the system displaces a plunger at constantforce.

FIG. 45 shows the surprising result that relatively smaller quantitiesof convection agents resulted in faster CO₂ generation. Experimentsshowed that the presence of about 10 mg of diatomaceous earth resultedin significantly faster CO2 generation than either 5 mg or 50 mg per ml.Thus, some preferable compositions comprise between 7 and 15 mg of aconvection agent or agents.

Example 11 Power Density

Power density of a variety of chemical engines were measured either at aconstant force or a constant volume.

Constant Force Setup:

Constant Force: A similar setup was used for constant force as constantvolume (described above), but the stage that the load cell was attachedto was able to move. The air cylinder was initially closed so that theinitial volume of the reactant chamber and connectors was 2.3 ml. Theair cylinder was allowed to move 1.4 inches (3.56). This distance waschosen because it was the amount that a piston would have to travel toempty a standard 2 ml syringe. The stage was initially pressurized to 18lbs, which corresponded to injecting 2 ml of 50 cp fluid using astandard 2 ml syringe with a 27 gauge, TW needle in 8 seconds.Additional measurements were obtained at 9 lbs of backpressure. Thiscorresponds to injecting 1 ml of 50 cp fluid using a standard 1 mlsyringe with a 27 gauge, TW needle at 8 seconds. The powder reactantswere placed into the reactant chamber and the liquid reactants were inthe syringe. The liquid reactants were injected into the chamber and thevalve was closed. Pressure, force, and temperature were measured untilthe air cylinder reached its travel distance, which was determined usingan LVDT (linear variable differential transformer) that was attached tothe stage. The apparatus is shown in FIG. 46.

The syringe labeled water in FIG. 46 could alternatively be an aqueoussolution comprising either acid or bicarbonate.

This test apparatus is applicable to test almost any chemical engine.Chemical engines that are integrated devices can be tested by placingthe entire device in the test apparatus. When testing an integral systemincluding a fluid compartment, the average force can be measureddirectly or calculated using the Hagen-Poiseuille equation. Chemicalengines that are detachable from a fluid compartment are first detachedprior to testing.

In the Table below, the water was added to a mixed powder of citric acidand bicarbonate in a 1:3 molar ratio.

Power Density Ratio:

Power Density was calculated at different backpressures and initialvolumes. Time is measured starting at the initiation of the reactionwhich is the time when acid and carbonate are combined with a solvent.For our case, Power Density=Average force*distance to end oftravel/(time to deliver*Volume of initial reactants)The volume used was the volume of the reactants all the reactantsdissolved and after CO2 has escaped. Open space within the reactionchamber that is not occupied by reactants or solvent is not taken intoaccount for our calculations.

Volume of Time to 3.56 cm Power Power Reactants Average DisplacementDensity Density Compartment 1 Compartment 2 (mL) Force (N) (seconds)(W/m{circumflex over ( )}3) Ratio 1 mL water 630 mg potassiumbicarbonate, 1.4 99.3 22.59 111,820 3.4 403 mg citric acid 1 mL water630 mg potassium bicarbonate, 1.4 89.4  8.46 268,765 8.1 403 mg citricacid, 10 mg diatomaceous earth 1 mL water 630 mg potassium bicarbonate,1.4 96.1  8.17 299,075 9.0 403 mg citric acid, 10 mg polyacrylonitrilehollow spheres 1 mL water, 403 mg 630 mg potassium bicarbonate 1.4 85.94.4 496,195 15.0 citric acid 1 mL water, 403 mg 630 mg potassiumbicarbonate, 1.4 81.8  2.95 704,809 21.3 citric acid 10 mg diatomaceousearth 1 mL water, 403 mg 630 mg potassium bicarbonate, 1.4 81.4  2.66778,247 23.5 citric acid 10 mg diatomaceous earth, mixing 1 mL water,403 mg 529 mg sodium bicarbonate 1.4 91.1 60*   33,056 Control citricacid 1 mL water 630 mg potassium bicarbonate, 1.4 40.9  3.94 264,143 1.4403 mg citric acid 1 mL water, 403 mg 630 mg potassium bicarbonate, 1.440.5 1.2 857,843 4.4 citric acid 10 mg diatomaceous earth 1 mL water,403 mg 529 m sodium bicarbonate 1.4 42.5  5.52 195,472 Control citricacid 0.5 mL water 315 mg potassium bicarbonate, 0.7 45.8 16.8  138,7096.0 202 mg citric acid 0.5 mL water, 315 mg potassium bicarbonate, 0.745.7 5.1 455,594 19.8 202 mg citric 10 mg diatomaceous earth, acidmixing 0.5 mL water, 264 mg sodium bicarbonate 0.7 44.5 60**  23,000Control 202 mg citric acid *Did not reach full displacement, so adisplacement of 3.05 cm at 60 s was used **Did not reach fulldisplacement, so a displacement of 2.17 cm at 60 s was used Example (Row1): Power Density = Average Force * Displacement/Time/Volume ofReactants 111,778 W/m{circumflex over ( )}3 = 99.3 N * 3.56 cm * (0.01m/cm)/22.59 s/1.4 mL * (0.000001 m{circumflex over ( )}3/mL) (Thenumbers do not match the table exactly because they were rounded forthis example.)In each of the above experiments, the molar ratio of bicarbonate tocitric acid is 3:1 (in general, for all of the systems described in thisapplication, preferred formulations have a molar ratio of bicarbonate tocitric acid in the range of 2 to 4, more preferably 2.5 to 3.5. Thepresent invention can be characterized by power density at roomtemperature, measured and calculated as described above and at a nominalback pressure of 9 lbs (40 N). At these conditions, the inventionpreferably has a power density of at least 50,000 W/m³, more preferablyat least 100,000 W/m³, more preferably at least 250,000 W/m³, morepreferably at least 400,000 W/m³, and in some embodiments an upper limitof 1,000,000 W/m³, or about 900,000 W/m³. Alternatively, the inventioncan be defined in terms of a power density by comparison with a controlformulation that is subjected to the same conditions. The controlformulation contains 1 mL water, 403 mg citric acid, and 529 mg sodiumbicarbonate. This control formulation is appropriate for reactionchamber volumes of about 2 mL; the power density of controls in chemicalengines which are larger or smaller than 2 ml should be tested with acontrol formulation that is adjusted in volume while maintaining thisproportion of water, sodium bicarbonate and citric acid. Again, asmeasured at a nominal back pressure of 9 lbs (40 N) and at constantforce, the inventive chemical engine preferably has a power densityratio of at least 1.4, more preferably at least 3 when compared to thecontrol; and in some embodiments a maximum power density ratio of 10 ora maximum of about 5, or a maximum of about 4.4. In preferredembodiments, displacement begins with 2 sec, more preferably within 1sec of the moment when acid, carbonate and solvent (water) are combined.It should be noted that the term “control” does not imply a conventionalformulation since conventional formulations for chemical engines weremuch more dilute. The control is typically tested to full displacement;however, in cases where full displacement is not achieved within 30seconds, the control is defined as the displacement within the first 30seconds.

1. A chemical engine, comprising: a closed container comprising an acid,bicarbonate, water, and a plunger; a mechanism adapted to combine theacid, the water, and the bicarbonate; and further characterized by apower density of at least 50,000 W/m³, as measured at a constant nominalbackpressure of 40 N, or a power density ratio of at least 1.4 ascompared to a control comprising a 3:1 molar ratio of sodium bicarbonateand citric acid and having a concentration of 403 mg citric acid in 1 gH₂O.
 2. The chemical engine of claim 1 characterized by a power densityof at least 250,000 W/m³.
 3. The chemical engine of claim 1characterized by a power density in the range of 100,000 W/m³ to 1×10⁶W/m³.
 4. The chemical engine of claim 1 characterized by a power densityratio with the control in the range of 1.4 to about
 5. 5. The chemicalengine of claim 1 wherein at least 50 wt % of the bicarbonate is asolid.
 6. The chemical engine of claim 1 wherein the bicarbonatecomprises at least 50 wt % potassium bicarbonate.
 7. The chemical engineof claim 1 wherein the closed container further comprises a convectionagent.
 8. The chemical engine of claim 1 wherein the closed containercomprises 1.5 mL or less of a liquid.
 9. The chemical engine of claim 1wherein the closed container has a total internal volume, prior tocombining the acid and the carbonate, of 2 mL or less.
 10. The chemicalengine of claim 1 wherein the bicarbonate comprises a solid mixture ofat least two types of particle morphologies.
 11. The chemical engine ofclaim 1 wherein the acid and the water are present as an acid solutioncomprising the acid dissolved in water, and wherein the acid solution isseparated from the bicarbonate.
 12. The chemical engine of claim 1wherein the acid and bicarbonate are present as solids and the water isseparated from the acid and the bicarbonate.
 13. A chemical engine,comprising: a closed container comprising an acid solution comprising anacid dissolved in water, and bicarbonate, wherein the acid solution isseparated from the solid bicarbonate, and a plunger; a conduitcomprising apertures disposed within the closed container and adaptedsuch that, following initiation, at least a portion of the acid solutionis forced through at least a portion of the apertures.
 14. The chemicalengine of claim 13 wherein the bicarbonate is in particulate form andwherein the conduit comprises a tube having one end that is disposed inthe solid bicarbonate such that, when the solution is forced through theapertures it contacts the solid bicarbonate particulate.
 15. Thechemical engine of claim 13 wherein at least a portion of thebicarbonate is in solid form disposed inside the conduit.
 16. Thechemical engine of claim 13 wherein chemical engine comprises a springthat is adapted to force the acid solution through the conduit.
 17. Achemical engine, comprising: a closed container comprising an acidsolution comprising an acid dissolved in water, and potassiumbicarbonate, wherein the acid solution is separated from the potassiumbicarbonate, and a plunger; and a mechanism adapted to combine the acidsolution and the potassium bicarbonate.
 18. The chemical engine of claim17 wherein the potassium bicarbonate is mixed with sodium bicarbonate.19. A chemical engine, comprising: a closed container comprising an acidsolution comprising an acid dissolved in water, solid bicarbonateparticles, and solid particulate convection agents, wherein the acidsolution is separated from the solid bicarbonate, and a plunger; amechanism adapted to combine the acid solution and the solidbicarbonate; wherein solid particulate convection agents are present: inthe range of less than 50 mg per ml of combined solution and at a levelselected such that, all other variables being held constant, thegeneration of CO₂ is faster during the first 5 seconds in which the acidsolution and solid bicarbonate are combined than the generation of CO₂in the presence of 50 mg per ml of the particulate convection agents; or5 mg to 25 mg per ml of combined solution.
 20. A chemical engine,comprising: a closed container comprising an acid solution comprising anacid dissolved in water, and solid bicarbonate particles, wherein theacid solution is separated from the solid bicarbonate, and a plunger; amechanism adapted to combine the acid solution and the solidbicarbonate; wherein the solid bicarbonate particles comprise a mixtureof particle morphologies.
 21. The chemical engine of claim 19 whereinthe solid bicarbonate particles are derived from at least two differentsources, a first source and a second source, and wherein the firstsource differs from the second source by at least 20% in one or more ofthe following characteristics: mass average particle size, surface areaper mass, solubility in water at 20° C. as measured by the time tocomplete dissolution into a 1 molar solution in equally stirredsolutions.
 22. A method of ejecting a liquid medicament from a syringe,comprising: providing a closed container comprising an acid solutioncomprising an acid dissolved in water, and bicarbonate, wherein the acidsolution is separated from the bicarbonate, and a plunger; wherein theacid solution and the bicarbonate in the container define a latent powerdensity; wherein the plunger separates the closed container from amedicament compartment; combining the acid solution and the bicarbonatewithin the closed container; wherein the acid solution and thebicarbonate react to generate CO₂ to power the plunger, which, in turn,pushes the liquid medicament from the syringe; wherein pressure withinthe container reaches a maximum within 10 seconds after initiation, andwherein, after 5 minutes, the latent power density is 20% or less of theinitial latent power density, and wherein, after 10 minutes, thepressure within the closed container is no more than 50% of the maximumpressure.
 23. The method of claim 22 wherein the closed containerfurther comprises a CO₂ removal agent that removes CO₂ at a rate that isat least 10 times slower than the maximum rate at which CO₂ is generatedin the reaction.
 24. A device for delivering a fluid by chemicalreaction, comprising: a reagent chamber having a plunger at an upper endand a one-way valve at a lower end, the one-way valve permitting exitfrom the reagent chamber; a reaction chamber having the one-way valve atan upper end and a piston at a lower end; and a fluid chamber having thepiston at an upper end, wherein the piston moves in response to pressuregenerated in the reaction chamber such that the volume of the reactionchamber increases and the volume of the fluid chamber decreases; whereinthe reaction chamber contains a dry acid powder and a release agent. 25.The device of claim 24, wherein the acid powder is citrate and therelease agent is sodium chloride.
 26. A device for delivering a fluid bychemical reaction, comprising: a barrel containing a reaction chamberand a fluid chamber which are separated by a moveable piston; and athermal source for heating the reaction chamber or a light source thatilluminates the reaction chamber.
 27. The device of claim 26, whereinthe reaction chamber contains at least one chemical reagent thatgenerates a gas upon exposure to light.
 28. A process for delivering ahigh-viscosity fluid by chemical reaction, comprising: initiating agas-generating chemical reaction in a reaction chamber of a device, thechamber including a piston; wherein the gas moves the piston into afluid chamber containing the high-viscosity fluid and delivers thehigh-viscosity fluid; and wherein the high-viscosity fluid is deliveredwith a constant pressure versus time profile.
 29. A device fordelivering a fluid by chemical reaction, comprising: a barrel containinga reagent chamber, a reaction chamber, and a fluid chamber; wherein thereagent chamber is located within a push button member at a top end ofthe barrel; a plunger separating the reagent chamber from the reactionchamber; a spring biased to push the plunger into the reagent chamberwhen the push button member is depressed; and a piston separating thereaction chamber from the fluid chamber, wherein the piston moves inresponse to pressure generated in the reaction chamber.
 30. The deviceof claim 29, wherein the push button member comprises a sidewall closedat an outer end by a contact surface, a lip extending outwards from aninner end of the sidewall, and a sealing member proximate a centralportion on an exterior surface of the sidewall.
 31. The device of claim29, wherein the plunger comprises a central body having lugs extendingradially therefrom, and a sealing member on an inner end which engages asidewall of the reaction chamber.
 32. The device of claim 31, wherein aninterior surface of the push button member includes channels for thelugs.
 33. The device of claim 29, wherein the reaction chamber isdivided into a mixing chamber and an arm by the interior radial surface,the interior radial surface having an orifice, and the piston beinglocated at the end of the arm.
 34. The device of claim 33, wherein themixing chamber includes a gas permeable filter covering the orifice. 35.A device for delivering a fluid by chemical reaction, comprising: anupper chamber having a seal at a lower end; a lower chamber having aport at an upper end, a ring of teeth at the upper end having the teethoriented towards the seal of the upper chamber, and a piston at a lowerend; and a fluid chamber having the piston at an upper end; wherein theupper chamber moves axially relative to the lower chamber; and whereinthe piston moves in response to pressure generated in the lower chambersuch that the volume of the reaction chamber increases and the volume ofthe fluid chamber decreases.
 36. The device of claim 35, wherein thepiston includes a head and a balloon that communicates with the port.37. The device of claim 35, wherein the ring of teeth surround the port.38. The device of claim 35, wherein the upper chamber travels within abarrel of the device.
 39. The device of claim 35, wherein the upperchamber is the lower end of a plunger.
 40. The device of claim 38,wherein the plunger includes a pressure lock that cooperates with a topend of the device to lock the upper chamber in place after beingdepressed.
 41. The device of claim 38, wherein the fluid chambercontains a high-viscosity fluid having a viscosity of at least 40centipoise.
 42. The device of claim 35, wherein the upper chambercontains a solvent.
 43. The device of claim 35, wherein the lowerchamber contains at least two chemical reagents that react with eachother to generate a gas.
 44. The device of claim 35, wherein the upperchamber, the lower chamber, and the fluid chamber are separate piecesthat are joined together to make the device.
 45. A device for deliveringa fluid by chemical reaction, comprising: an upper chamber; a lowerchamber having a piston at a lower end; a fluid chamber having thepiston at an upper end; and a plunger comprising a shaft that runsthrough the upper chamber, a stopper at a lower end of the shaft, and athumbrest at an upper end of the shaft, the stopper cooperating with aseat to separate the upper chamber and the lower chamber; whereinpulling the plunger causes the stopper to separate from the seat andcreate fluid communication between the upper chamber and the lowerchamber; and wherein the piston moves in response to pressure generatedin the lower chamber such that the volume of the reaction chamberincreases and the volume of the fluid chamber decreases.
 46. The deviceof claim 45, wherein the fluid chamber contains a high-viscosity fluidhaving a viscosity of at least 40 centipoise.
 47. The device of claim45, wherein the upper chamber contains a solvent.
 48. The device ofclaim 45, wherein the lower chamber contains at least two chemicalreagents that react with each other to generate a gas.
 49. The device ofclaim 45, wherein the upper chamber, the lower chamber, and the fluidchamber are separate pieces that are joined together to make the device.50. The device of claim 45, wherein either the upper chamber or thelower chamber contains an encapsulated reagent.
 51. A device fordelivering a fluid by chemical reaction, comprising: a reaction chamberdivided by a barrier into a first compartment and a second compartment,the first compartment containing at least two dry chemical reagents thatcan react with each other to generate a gas, and the second compartmentcontaining a solvent; and a fluid chamber having an outlet; whereinfluid in the fluid chamber exits through the outlet in response topressure generated in the reaction chamber.
 52. The device of claim 51,wherein pressure generated in the reaction chamber acts on a piston inthe fluid chamber to cause fluid to exit through the outlet.
 53. Thedevice of claim 51, wherein the reaction chamber is formed from asidewall, the fluid chamber is formed from a sidewall, and the reactionchamber and the fluid chamber are fluidly connected at a first end ofthe device.
 54. The device of claim 51, wherein the reaction chamberincludes a flexible wall, proximate to the fluid chamber; and whereinthe fluid chamber is formed from a flexible sidewall, such that pressuregenerated in the reaction chamber causes the flexible wall to expand andcompress the flexible sidewall of the fluid chamber, causing fluid toexit through the outlet.
 55. The device of claim 51, wherein thereaction chamber and the fluid chamber are surrounded by a housing. 56.The device of claim 54, wherein the reaction chamber and the fluidchamber are side-by-side in the housing.
 57. The device of claim 54,wherein a needle extends from a bottom of the housing and is fluidlyconnected to the outlet of the fluid chamber; and wherein the reactionchamber is located on top of the fluid chamber.
 58. A device fordelivering a fluid by chemical reaction, comprising: an upper chamberhaving a stationary one-way valve at a lower end, the one-way valvepermitting exit from the upper chamber; a plunger which can travelthrough only the upper chamber; a lower chamber having the stationaryone-way valve at an upper end and a piston at a lower end; and a fluidchamber having the piston at an upper end; wherein the piston moves inresponse to pressure generated in the lower chamber such that the volumeof the reaction chamber increases and the volume of the fluid chamberdecreases.
 59. The device of claim 58, wherein the fluid chambercontains a high-viscosity fluid having a viscosity of at least 40centipoise.
 60. The device of claim 58, wherein the upper chambercontains a solvent.
 61. The device of claim 58, wherein the piston isformed from a push surface at the lower end of the lower chamber and ahead at the upper end of the fluid chamber, and optionally includes arod connecting the push surface and the head.
 62. The device of claim58, wherein the plunger includes a thumbrest and a pressure lock thatcooperates with the upper chamber to lock the plunger in place afterbeing depressed.
 63. The device of claim 62, wherein the pressure lockis proximate the thumbrest and cooperates with an upper surface of theupper chamber.
 64. The device of claim 62, wherein the lower chamber isdefined by the one-way valve, a continuous sidewall, and the piston, theone-way valve and the sidewall being fixed relative to each other suchthat the volume of the lower chamber changes only through movement ofthe piston.
 65. The device of claim 62, wherein the upper chamber, thelower chamber, and the fluid chamber are cylindrical and are coaxial.66. The device of claim 62, wherein the upper chamber, the lowerchamber, and the fluid chamber are separate pieces that are joinedtogether to make the device.
 67. The device of claim 62, wherein theone-way valve feeds a balloon in the lower chamber, the balloon pushingthe piston.